1-heterocyclyl isochromanyl compounds and analogs for treating CNS disorders

ABSTRACT

Disclosed are compounds of Formula (I):and pharmaceutically acceptable salts thereof, wherein A, Ra, R1, R2, R3, R4, R6, w and n1 are defined and described herein; compositions thereof; and methods of use thereof. These compounds are useful for treating a variety of neurological and psychiatric disorders, such as those described herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 15/819,372 filed Nov. 21, 2017, now allowed, which is a divisionalof U.S. patent application Ser. No. 15/041,852, filed Feb. 11, 2016,which issued as U.S. Pat. No. 9,856,238 on Jan. 2, 2018, which claimsthe benefit of U.S. Provisional Application No. 62/115,064, filed Feb.11, 2015. The disclosures of each of these prior applications are herebyincorporated herein by reference in their entirety.

BACKGROUND

Central nervous system disorders affect a wide range of the populationwith differing severity. Neurological and psychiatric disorders includemajor depression, schizophrenia, bipolar disorder, obsessive compulsivedisorder (OCD), panic disorder, and posttraumatic stress disorder(PTSD), among others. These disorders affect a person's thoughts, mood,behavior and social interactions and can significantly impair dailyfunctioning. See, e.g., Diagnostic and Statistical Manual of MentalDisorders, 4th Ed., American Psychiatric Association (2000)(“DSM-IV-TR”); Diagnostic and Statistical Manual of Mental Disorders,5th Ed., American Psychiatric Association (2013) (“DSM-5”).

Bipolar disorder is a serious psychiatric disorder that has a prevalenceof approximately 2% of the population, and affects both genders alike.It is a relapsing-remitting condition characterized by cycling betweenelevated (i.e., manic) and depressed moods, which distinguishes it fromother disorders such as major depressive disorder and schizophrenia.Bipolar I is defined by the occurrence of a full manic episode, althoughmost individuals experience significant depression. Symptoms of maniainclude elevated or irritable mood, hyperactivity, grandiosity,decreased need for sleep, racing thoughts and in some cases, psychosis.The depressive episodes are characterized by anhedonia, sad mood,hopelessness, poor self-esteem, diminished concentration and lethargy.Bipolar II is defined as the occurrence of a major depressive episodeand hypomanic (less severe mania) episode although patients spendconsiderable more time in the depressive state. Other related conditionsinclude cyclothymic disorder.

Schizophrenia is a psychopathic disorder of unknown origin, whichusually appears for the first time in early adulthood and is marked bycharacteristics such as psychotic symptoms, phasic progression anddevelopment, and/or deterioration in social behavior and professionalcapability. Characteristic psychotic symptoms are disorders of thoughtcontent (e.g., multiple, fragmentary, incoherent, implausible or simplydelusional contents, or ideas of persecution) and of mentality (e.g.,loss of association, flight of imagination, incoherence up toincomprehensibility), as well as disorders of perceptibility (e.g.,hallucinations), emotions (e.g., superficial or inadequate emotions),self-perceptions, intentions, impulses, and/or inter-humanrelationships, and psychomotoric disorders (e.g., catatonia). Othersymptoms are also associated with this disorder.

Schizophrenia is classified into subgroups: the paranoid type,characterized by delusions and hallucinations and absence of thoughtdisorder, disorganized behavior, and affective flattening; thedisorganized type, also named “hebephrenic schizophrenia,” in whichthought disorder and flat affect are present together; the cataconictype, in which prominent psychomotor disturbances are evident, andsymptoms may include catatonic stupor and waxy flexibility; and theundifferentiated type, in which psychotic symptoms are present but thecriteria for paranoid, disorganized, or catatonic types have not beenmet. The symptoms of schizophrenia normally manifest themselves in threebroad categories: positive, negative and cognitive symptoms. Positivesymptoms are those which represent an “excess” of normal experiences,such as hallucinations and delusions. Negative symptoms are those wherethe patient suffers from a lack of normal experiences, such as anhedoniaand lack of social interaction. The cognitive symptoms relate tocognitive impairment in schizophrenics, such as lack of sustainedattention and deficits in decision making.

Neurological and psychiatric disorders can exhibit a variety ofsymptoms, including cognitive impairment, depressive disorders, andanxiety disorders.

Cognitive impairment includes a decline in cognitive functions orcognitive domains, e.g., working memory, attention and vigilance, verballearning and memory, visual learning and memory, reasoning and problemsolving (e.g., executive function, speed of processing and/or socialcognition). In particular, cognitive impairment may indicate deficits inattention, disorganized thinking, slow thinking, difficulty inunderstanding, poor concentration, impairment of problem solving, poormemory, difficulties in expressing thoughts, and/or difficulties inintegrating thoughts, feelings and behavior, or difficulties inextinction of irrelevant thoughts.

Depressive disorders include major depressive disorder and dysthymia,and are associated with depressed mood (sadness), poor concentration,insomnia, fatigue, appetite disturbances, excessive guilt and thoughtsof suicide.

Anxiety disorders are disorders characterized by fear, worry, anduneasiness, usually generalized and unfocused as an overreaction to asituation. Anxiety disorders differ in the situations or types ofobjects that induce fear, anxiety, or avoidance behavior, and theassociated cognitive ideation. Anxiety differs from fear in that anxietyis an emotional response to a perceived future threat while fear isassociated with a perceived or real immediate threat. They also differin the content of the associated thoughts or beliefs.

SUMMARY

While medications exist for some aspects of these diseases, thereremains a need for effective treatments for various neurological andpsychiatric disorders, including mood disorders such as bipolar andrelated disorders, psychosis and schizophrenia. For example, while moodstabilizers such as lithium and valproate, antidepressants andantipsychotic drugs are used to treat mood disorders, more effectivemedications are necessary. And current antipsychotics may be successfulin treating the positive symptoms of schizophrenia but fare less wellfor the negative and cognitive symptoms. Additionally, currentantidepressants are typically effective only for a proportion ofpatients suffering from depression.

In some embodiments, the present invention encompasses the insight thatcompounds of Formula (I):

and pharmaceutically acceptable salts thereof, wherein A, R^(a), R¹, R²,R³, R⁴, R⁶, w and n1 are defined and described herein, are useful fortreating a variety of neurological and psychiatric disorders, such asthose described herein.

Also provided herein are methods for the treatment of variousneurological and psychiatric disorders using the compounds andcompositions provided herein.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCompounds of the Invention

In some embodiments, the present invention provides a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   A is

-   -   m is 0, 1, or 2;    -   n1 is 1, 2, or 3;    -   n2 is 0 or 1;    -   n3 is 0 or 1;    -   R is —H or C₁-C₃ alkyl;    -   R^(a) is —H or C₁-C₃ alkyl;    -   R¹, R², R³, and R⁴ are independently —H, halo, —OH, —NH₂, C₁-C₃        alkyl, —OR⁷, —NHR⁷, —N(R⁷)R⁷, —CN, phenyl, or 5- or 6-membered        heteroaryl, wherein:        -   each instance of R⁷ independently is unsubstituted C₁-C₂            alkyl or C₁-C₂ alkyl substituted with 1-3 halo,        -   each instance of C₁-C₃ alkyl independently is unsubstituted            or substituted with 1-3 halo,        -   and        -   the phenyl or heteroaryl is unsubstituted or substituted            with 1 or 2 groups independently selected from halo, —OH,            —OCH₃, —OCF₃, —NH₂, —NH(CH₃), —N(CH₃)₂, —CH₃, ethyl, —CF₃,            and —CN,    -   optionally wherein        -   two adjacent instances of R¹, R², R³, and R⁴ together form            —O—CH₂—O—, —O—CH(CH₃)—O—, —O—C(CH₃)₂—O—, —O—CH₂—CH₂—O—, or            —O—C(CH₃)₂—C(CH₃)₂—O—;    -   each instance of R⁵ independently is halo, —CH₃, or ethyl;    -   each instance of R⁶ independently is halo, —CH₃, ethyl or —OH;    -   w is 0, 1, or 2; and    -   Z is C or O;    -   provided that the compound is not

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75th Ed.Additionally, general principles of organic chemistry are described inM. Loudon, Organic Chemistry, 5th Ed., Roberts and Company, GreenwoodVillage, Colo.: 2009; and M. B. Smith, March's Advanced OrganicChemistry: Reactions, Mechanisms and Structure, 7th Ed., John Wiley &Sons, Hoboken: 2013, the entire contents of which are herebyincorporated by reference.

As used herein, the term “halogen” or “halo” means F, Cl, Br, or I.

As used herein, the term “alkylene” refers to a bivalent alkyl group. An“alkylene chain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein nis a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3,from 1 to 2, or from 2 to 3. A substituted alkylene chain is apolymethylene group in which one or more methylene hydrogen atoms arereplaced with a substituent. Suitable substituents include thosedescribed herein for a substituted aliphatic group.

As used herein, the terms “heteroaryl” and “heteroar-,” used alone or aspart of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,”refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ringatoms; having 6, 10, or 14π electrons shared in a cyclic array; andhaving, in addition to carbon atoms, from one to five ring heteroatoms.Heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, andpteridinyl. A heteroaryl group may be monocyclic or bicyclic. The term“heteroaryl” may be used interchangeably with the terms “heteroarylring,” “heteroaryl group,” or “heteroaromatic,” any of which termsinclude rings that are optionally substituted. The term “heteroaralkyl”refers to an alkyl group substituted by a heteroaryl, wherein the alkyland heteroaryl portions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to ring carbon atoms, one to four ringheteroatoms. When used in reference to a ring atom of a heterocycle, theterm “nitrogen” includes a substituted nitrogen. As an example, in asaturated or partially unsaturated ring having 0-3 heteroatoms selectedfrom oxygen, sulfur and nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as inN-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals includetetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl,pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein. A heterocyclyl group may be monocyclic orbicyclic. The term “heterocyclylalkyl” refers to an alkyl groupsubstituted by a heterocyclyl, wherein the alkyl and heterocyclylportions independently are optionally substituted.

As used herein, the term “unsaturated,” as used herein, means that amoiety has one or more units of unsaturation.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As used herein, the term “heteroatom” means one or more of oxygen,sulfur, nitrogen, phosphorus, or silicon (including, any oxidized formof nitrogen, sulfur, phosphorus, boron, or silicon; the quaternized formof any basic nitrogen; or a substitutable nitrogen of a heterocyclicring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)).

As used herein, the term “aryl” used alone or as part of a larger moietyas in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to carbocyclicaromatic ring systems having a total of six to fourteen ring atoms. Theterm “aryl” may be used interchangeably with the term “aryl ring.”Examples of “aryl” groups include phenyl, naphthyl, anthracyl and thelike, which may be optionally substituted.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N+(C₁₋₄ alkyl)₄ salts. Representative alkalior alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention.

Unless otherwise specified, the word “includes” (or any variationthereon, e.g., “include”, “including”, etc.) is intended to beopen-ended. For example, “A includes 1, 2 and 3” means that A includesbut is not limited to 1, 2 and 3.

Unless otherwise specified, the phrase “such as” is intended to beopen-ended. For example, “A can be a halogen, such as chlorine orbromine” means that A can be, but is not limited to, chlorine orbromine.

3. Description of Exemplary Embodiments

In some embodiments, the present invention provides a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   A is

-   -   m is O, 1, or 2;    -   n1 is 1, 2, or 3;    -   n2 is 0 or 1;    -   n3 is 0 or 1;    -   R is —H or C₁-C₃ alkyl;    -   R^(a) is —H or C₁-C₃ alkyl;    -   R¹, R², R³, and R⁴ are independently —H, halo, —OH, —NH₂, C₁-C₃        alkyl, —OR⁷, —NHR⁷, —N(R⁷)R⁷, —CN, phenyl, or 5- or 6-membered        heteroaryl, wherein:        -   each instance of R⁷ independently is unsubstituted C₁-C₂            alkyl or C₁-C₂ alkyl substituted with 1-3 halo,        -   each instance of C₁-C₃ alkyl independently is unsubstituted            or substituted with 1-3 halo,        -   and        -   the phenyl or heteroaryl is unsubstituted or substituted            with 1 or 2 groups independently selected from halo, —OH,            —OCH₃, —OCF₃, —NH₂, —NH(CH₃), —N(CH₃)₂, —CH₃, ethyl, —CF₃,            and —CN,        -   optionally wherein            -   two adjacent instances of R¹, R², R³, and R⁴ together                form —O—CH₂—O—, —O—CH(CH₃)—O—, —O—C(CH₃)₂—O—,                —O—CH₂—CH₂—O—, or —O—C(CH₃)₂—C(CH₃)₂—O—;    -   each instance of R⁵ independently is halo, —CH₃, or ethyl;    -   each instance of R⁶ independently is halo, —CH₃, ethyl or —OH;    -   w is 0, 1, or 2; and    -   Z is C or O;    -   with the proviso that the compound is not:

Such a compound (including pharmaceutically acceptable salts) isreferred to herein as a “provided compound”. Provided compounds are alsodescribed in U.S. Application No. 62/115,064, filed Feb. 11, 2015, whichis hereby incorporated by reference herein in its entirety.

As defined above, A is

In some embodiments, A is

As defined above, m is 0, 1, or 2. In some embodiments, m is 0. In someembodiments, m is 1. In some embodiments, m is 2. In some embodiments, mis 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0or 2.

As defined above, n1 is 1, 2, or 3. In some embodiments, n1 is 1. Insome embodiments, n1 is 2. In some embodiments, n1 is 3. In someembodiments, n1 is 1 or 2. In some embodiments, n1 is 1 or 3. In someembodiments, n1 is 2 or 3.

As defined above, n2 is 0 or 1. In some embodiments, n2 is 0. In someembodiments, n2 is 1.

As defined above, n3 is 0 or 1. In some embodiments, n3 is 0. In someembodiments, n3 is 1.

As defined above, R is —H or C₁-C₃ alkyl. In some embodiments, R is —H.In some embodiments, R is C₁-C₃ alkyl. In some embodiments, R is —H or—CH₃.

As defined above, R^(a) is —H or C₁-C₃ alkyl. In some embodiments, R^(a)is —H. In some embodiments, R^(a) is C₁-C₃ alkyl. In some embodiments,R^(a) is —H or —CH₃.

As defined above, R¹, R², R³, and R⁴ are independently —H, halo, —OH,—NH₂, C₁-C₃ alkyl, —OR⁷, —NHR⁷, —N(R⁷)R⁷, —CN, phenyl, or 5- or6-membered heteroaryl, wherein:

each instance of R⁷ independently is unsubstituted C₁-C₂ alkyl or C₁-C₂alkyl substituted with 1-3 halo,

each instance of C₁-C₃ alkyl independently is unsubstituted orsubstituted with 1-3 halo, and

the phenyl or heteroaryl is unsubstituted or substituted with 1 or 2groups independently selected from halo, —OH, —OCH₃, —OCF₃, —NH₂,—NH(CH₃), —N(CH₃)₂, —CH₃, ethyl, —CF₃, and —CN,

optionally wherein two adjacent instances of R¹, R², R³, and R⁴ togetherform —O—CH₂—O—, —O—CH(CH₃)—O—, —O—C(CH₃)₂—O—, —O—CH₂—CH₂—O—, or—O—C(CH₃)₂—C(CH₃)₂—O—

In some embodiments, at least two of R¹, R², R³, and R⁴ are —H. In someembodiments, at least three of R¹, R², R³, and R⁴ are —H. In someembodiments, the 5- or 6-membered heteroaryl of R¹, R², R³, and R⁴ hasat least 1 nitrogen ring atom and is unsubstituted or substituted with 1group selected from halo, —OH, —OCH₃, —OCF₃, —NH₂, —NH(CH₃), —N(CH₃)₂,—CH₃, ethyl, —CF₃, and —CN. In some embodiments, the 5- or 6-memberedheteroaryl of R¹, R², R³, and R⁴ is unsubstituted pyridyl, pyrimidinyl,pyrrolyl, pyrazolyl, isoxazolyl, imidazolyl, or oxazolyl. In someembodiments, the 5- or 6-membered heteroaryl of R¹, R², R³, and R⁴ isunsubstituted pyridyl or isoxazolyl. In some embodiments, two adjacentinstances of R¹, R², R³, and R⁴ together form —O—CH₂—O—, —O—CH(CH₃)—O—,or —O—C(CH₃)₂—O—. In some embodiments, two adjacent instances of R¹, R²,R³, and R⁴ together form —O—CH₂—O—. In some embodiments, R¹, R², R³, andR⁴ are independently —H, halo, C₁-C₃ alkyl, —OR⁷ or —CN. In someembodiments, R¹, R², R³, and R⁴ are independently —H, —F, —CH₃, —OCH₃,or —CN.

As defined above, each instance of R⁵ independently is halo, —CH₃, orethyl. In some embodiments, each instance of R⁵ independently is halo.In some embodiments, each instance of R⁵ independently is —CH₃. In someembodiments, each instance of R⁵ independently is ethyl. In someembodiments, each instance of R⁵ independently is halo or —CH₃. In someembodiments, each instance of R⁵ independently is halo or ethyl. In someembodiments, each instance of R⁵ independently is —CH₃ or ethyl. In someembodiments, each instance of R⁵ independently is —F or —CH₃.

As defined above, each instance of R⁶ independently is halo, —CH₃, ethylor —OH. In some embodiments, each instance of R⁶ independently is halo.In some embodiments, each instance of R⁶ independently is —CH₃. In someembodiments, each instance of R⁶ independently is ethyl. In someembodiments, each instance of R⁶ independently is —OH. In someembodiments, each instance of R⁶ independently is halo or —CH₃. In someembodiments, each instance of R⁶ independently is halo or ethyl. In someembodiments, each instance of R⁶ independently is —CH₃ or ethyl. In someembodiments, each instance of R⁶ independently is —F or —CH₃.

As defined above, w is 0, 1, or 2. In some embodiments, w is 0. In someembodiments, w is 1. In some embodiments, w is 2. In some embodiments, wis 0 or 1. In some embodiments, w is 1 or 2. In some embodiments, w is 0or 2.

As defined above, Z is C or O. In some embodiments, Z is C. In someembodiments, Z is O.

In some embodiments, a provided compound is a compound of formula (I-A)or (I-B):

or a pharmaceutically acceptable salt thereof, wherein each of m, n1,n2, n3, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, w, and Z is as described inembodiments for formula I, supra, or described in embodiments herein,both singly and in combination.

In some embodiments, a provided compound is a compound of formula (I-A1)or (I-B1):

or a pharmaceutically acceptable salt thereof, wherein each of m, n2,n3, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, w, and Z is as described inembodiments for formula I, supra, or described in embodiments herein,both singly and in combination.

In some embodiments, a provided compound is a compound of formula (I-A2)or (I-B2):

or a pharmaceutically acceptable salt thereof, wherein each of m, n2,n3, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, w, and Z is as described inembodiments for formula I, supra, or described in embodiments herein,both singly and in combination.

In some embodiments, a provided compound is a compound of formula (I-A3)or (I-B3):

or a pharmaceutically acceptable salt thereof, wherein each of m, n2,n3, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, w, and Z is as described inembodiments for formula I, supra, or described in embodiments herein,both singly and in combination.

In some embodiments, a provided compound is a compound of formula (I-A),or a pharmaceutically acceptable salt thereof, wherein each of m, n1,n2, n3, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, w, and Z is as described inembodiments for formula I, supra, or described in embodiments herein,both singly and in combination. In some such embodiments, Z is C. Insome such embodiments, Z is C, n2 is 0 and n3 is 0. In some suchembodiments, Z is C, and one of n2 and n3 is 0 and the other is 1. Insome such embodiments, Z is C, n2 is 1 and n3 is 1. In some suchembodiments, at least two of R¹, R², R³, and R⁴ are —H. In some suchembodiments, at least three of R¹, R², R³, and R⁴ are —H. In some suchembodiments, R^(a) is —H. In some such embodiments, R is —H. In somesuch embodiments, R^(a) is —H and R is —H. In some such embodiments,each instance of R⁵ is —F or —CH₃. In some such embodiments, R^(a) is—H, R is —H, and each instance of R⁵ is —F or —CH₃. In some suchembodiments, each instance of R⁶ is —F or —CH₃. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;and each instance of R⁶ is —F or —CH₃. In some such embodiments, eachinstance of R⁶ is —CH₃. In some such embodiments, R^(a) is —H; R is —H;each instance of R⁵ is —F or —CH₃; and each instance of R⁶ is —CH₃. Insome such embodiments, m is 0. In some such embodiments, R^(a) is —H; Ris —H; each instance of R⁵ is —F or —CH₃; each instance of R⁶ is —F or—CH₃; and m is 0. In some such embodiments, w is 0. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;each instance of R⁶ is —F or —CH₃; m is 0; and w is 0. In some suchembodiments, R¹, R², R³, and R⁴ are independently —H, halo, C₁-C₃ alkyl,—OR⁷ or —CN. In some such embodiments, w is 0. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and R¹, R², R³, and R⁴ areindependently —H, halo, C₁-C₃ alkyl, —OR⁷ or —CN. In some suchembodiments, two adjacent instances of R¹, R², R³, and R⁴ together form—O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and two adjacent instances of R¹,R², R³, and R⁴ together form —O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—.

In some embodiments, a provided compound is a compound of formula(I-A1), (I-A2), or (I-A3), or a pharmaceutically acceptable saltthereof, wherein each of m, n2, n3, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, w,and Z is as described in embodiments for formula I, supra, or describedin embodiments herein, both singly and in combination. In some suchembodiments, Z is C. In some such embodiments, Z is C, n2 is 0 and n3 is0. In some such embodiments, Z is C, and one of n2 and n3 is 0 and theother is 1. In some such embodiments, Z is C, n2 is 1 and n3 is 1. Insome such embodiments, at least two of R¹, R², R³, and R⁴ are —H. Insome such embodiments, at least three of R¹, R², R³, and R⁴ are —H. Insome such embodiments, R^(a) is —H. In some such embodiments, R is —H.In some such embodiments, R^(a) is —H and R is —H. In some suchembodiments, each instance of R⁵ is —F or —CH₃. In some suchembodiments, R^(a) is —H, R is —H, and each instance of R⁵ is —F or—CH₃. In some such embodiments, each instance of R⁶ is —F or —CH₃. Insome such embodiments, R^(a) is —H; R is —H; each instance of R⁵ is —For —CH₃; and each instance of R⁶ is —F or —CH₃. In some suchembodiments, each instance of R⁶ is —CH₃. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; and eachinstance of R⁶ is —CH₃. In some such embodiments, m is 0. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;each instance of R⁶ is —F or —CH₃; and m is 0. In some such embodiments,w is 0. In some such embodiments, R^(a) is —H; R is —H; each instance ofR⁵ is —F or —CH₃; each instance of R⁶ is —F or —CH₃; m is 0; and w is 0.In some such embodiments, R¹, R², R³, and R⁴ are independently —H, halo,C₁-C₃ alkyl, —OR⁷ or —CN. In some such embodiments, w is 0. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;each instance of R⁶ is —F or —CH₃; m is 0; w is 0; and R¹, R², R³, andR⁴ are independently —H, halo, C₁-C₃ alkyl, —OR⁷ or —CN. In some suchembodiments, two adjacent instances of R¹, R², R³, and R⁴ together form—O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and two adjacent instances of R¹,R², R³, and R⁴ together form —O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—.

In some embodiments, a provided compound is a compound of formula (I-B),or a pharmaceutically acceptable salt thereof, wherein each of m, n1,n2, n3, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, w, and Z is as described inembodiments for formula I, supra, or described in embodiments herein,both singly and in combination. In some such embodiments, Z is C. Insome such embodiments, Z is C, n2 is 0 and n3 is 0. In some suchembodiments, Z is C, and one of n2 and n3 is 0 and the other is 1. Insome such embodiments, Z is C, n2 is 1 and n3 is 1. In some suchembodiments, at least two of R¹, R², R³, and R⁴ are —H. In some suchembodiments, at least three of R¹, R², R³, and R⁴ are —H. In some suchembodiments, R^(a) is —H. In some such embodiments, R is —H. In somesuch embodiments, R^(a) is —H and R is —H. In some such embodiments,each instance of R⁵ is —F or —CH₃. In some such embodiments, R^(a) is—H, R is —H, and each instance of R⁵ is —F or —CH₃. In some suchembodiments, each instance of R⁶ is —F or —CH₃. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;and each instance of R⁶ is —F or —CH₃. In some such embodiments, eachinstance of R⁶ is —CH₃. In some such embodiments, R^(a) is —H; R is —H;each instance of R⁵ is —F or —CH₃; and each instance of R⁶ is —CH₃. Insome such embodiments, m is 0. In some such embodiments, R^(a) is —H; Ris —H; each instance of R⁵ is —F or —CH₃; each instance of R⁶ is —F or—CH₃; and m is 0. In some such embodiments, w is 0. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;each instance of R⁶ is —F or —CH₃; m is 0; and w is 0. In some suchembodiments, R¹, R², R³, and R⁴ are independently —H, halo, C₁-C₃ alkyl,—OR⁷ or —CN. In some such embodiments, w is 0. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and R¹, R², R³, and R⁴ areindependently —H, halo, C₁-C₃ alkyl, —OR⁷ or —CN. In some suchembodiments, two adjacent instances of R¹, R², R³, and R⁴ together form—O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and two adjacent instances of R¹,R², R³, and R⁴ together form —O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—.

In some embodiments, a provided compound is a compound of formula(I-B1), (I-B2), or (I-B3), or a pharmaceutically acceptable saltthereof, wherein each of m, n2, n3, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, w,and Z is as described in embodiments for formula I, supra, or describedin embodiments herein, both singly and in combination. In some suchembodiments, Z is C. In some such embodiments, Z is C, n2 is 0 and n3 is0. In some such embodiments, Z is C, and one of n2 and n3 is 0 and theother is 1. In some such embodiments, Z is C, n2 is 1 and n3 is 1. Insome such embodiments, at least two of R¹, R², R³, and R⁴ are —H. Insome such embodiments, at least three of R¹, R², R³, and R⁴ are —H. Insome such embodiments, R^(a) is —H. In some such embodiments, R is —H.In some such embodiments, R^(a) is —H and R is —H. In some suchembodiments, each instance of R⁵ is —F or —CH₃. In some suchembodiments, R^(a) is —H, R is —H, and each instance of R⁵ is —F or—CH₃. In some such embodiments, each instance of R⁶ is —F or —CH₃. Insome such embodiments, R^(a) is —H; R is —H; each instance of R⁵ is —For —CH₃; and each instance of R⁶ is —F or —CH₃. In some suchembodiments, each instance of R⁶ is —CH₃. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; and eachinstance of R⁶ is —CH₃. In some such embodiments, m is 0. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;each instance of R⁶ is —F or —CH₃; and m is 0. In some such embodiments,w is 0. In some such embodiments, R^(a) is —H; R is —H; each instance ofR⁵ is —F or —CH₃; each instance of R⁶ is —F or —CH₃; m is 0; and w is 0.In some such embodiments, R¹, R², R³, and R⁴ are independently —H, halo,C₁-C₃ alkyl, —OR⁷ or —CN. In some such embodiments, w is 0. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;each instance of R⁶ is —F or —CH₃; m is 0; w is 0; and R¹, R², R³, andR⁴ are independently —H, halo, C₁-C₃ alkyl, —OR⁷ or —CN. In some suchembodiments, two adjacent instances of R¹, R², R³, and R⁴ together form—O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and two adjacent instances of R¹,R², R³, and R⁴ together form —O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—.

In some embodiments, a provided compound is a compound of formula (Ia),(Ib), (Ic), or (Id):

or a pharmaceutically acceptable salt thereof, wherein each of m, n1,n2, n3, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, w, and Z is as described inembodiments for formula I, supra, or described in embodiments herein,both singly and in combination, and where the depictions ofstereochemistry at the stereocenters marked with an asterisk (*) areabsolute.

In some embodiments, a provided compound is a compound of formula (Ia),or a pharmaceutically acceptable salt thereof, wherein each of m, n1,n2, n3, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, w, and Z is as described inembodiments for formula I, supra, or described in embodiments herein,both singly and in combination. In some such embodiments, Z is C. Insome such embodiments, Z is C, n2 is 0 and n3 is 0. In some suchembodiments, Z is C, and one of n2 and n3 is 0 and the other is 1. Insome such embodiments, Z is C, n2 is 1 and n3 is 1. In some suchembodiments, at least two of R¹, R², R³, and R⁴ are —H. In some suchembodiments, at least three of R¹, R², R³, and R⁴ are —H. In some suchembodiments, R^(a) is —H. In some such embodiments, R is —H. In somesuch embodiments, R^(a) is —H and R is —H. In some such embodiments,each instance of R⁵ is —F or —CH₃. In some such embodiments, R^(a) is—H, R is —H, and each instance of R⁵ is —F or —CH₃. In some suchembodiments, each instance of R⁶ is —F or —CH₃. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;and each instance of R⁶ is —F or —CH₃. In some such embodiments, eachinstance of R⁶ is —CH₃. In some such embodiments, R^(a) is —H; R is —H;each instance of R⁵ is —F or —CH₃; and each instance of R⁶ is —CH₃. Insome such embodiments, m is 0. In some such embodiments, R^(a) is —H; Ris —H; each instance of R⁵ is —F or —CH₃; each instance of R⁶ is —F or—CH₃; and m is 0. In some such embodiments, w is 0. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;each instance of R⁶ is —F or —CH₃; m is 0; and w is 0. In some suchembodiments, R¹, R², R³, and R⁴ are independently —H, halo, C₁-C₃ alkyl,—OR⁷ or —CN. In some such embodiments, w is 0. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and R¹, R², R³, and R⁴ areindependently —H, halo, C₁-C₃ alkyl, —OR⁷ or —CN. In some suchembodiments, two adjacent instances of R¹, R², R³, and R⁴ together form—O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and two adjacent instances of R¹,R², R³, and R⁴ together form —O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—.

In some embodiments, a provided compound is a compound of formula (Ib),or a pharmaceutically acceptable salt thereof, wherein each of m, n1,n2, n3, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, w, and Z is as described inembodiments for formula I, supra, or described in embodiments herein,both singly and in combination. In some such embodiments, Z is C. Insome such embodiments, Z is C, n2 is 0 and n3 is 0. In some suchembodiments, Z is C, and one of n2 and n3 is 0 and the other is 1. Insome such embodiments, Z is C, n2 is 1 and n3 is 1. In some suchembodiments, at least two of R¹, R², R³, and R⁴ are —H. In some suchembodiments, at least three of R¹, R², R³, and R⁴ are —H. In some suchembodiments, R^(a) is —H. In some such embodiments, R is —H. In somesuch embodiments, R^(a) is —H and R is —H. In some such embodiments,each instance of R⁵ is —F or —CH₃. In some such embodiments, R^(a) is—H, R is —H, and each instance of R⁵ is —F or —CH₃. In some suchembodiments, each instance of R⁶ is —F or —CH₃. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;and each instance of R⁶ is —F or —CH₃. In some such embodiments, eachinstance of R⁶ is —CH₃. In some such embodiments, R^(a) is —H; R is —H;each instance of R⁵ is —F or —CH₃; and each instance of R⁶ is —CH₃. Insome such embodiments, m is 0. In some such embodiments, R^(a) is —H; Ris —H; each instance of R⁵ is —F or —CH₃; each instance of R⁶ is —F or—CH₃; and m is 0. In some such embodiments, w is 0. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;each instance of R⁶ is —F or —CH₃; m is 0; and w is 0. In some suchembodiments, R¹, R², R³, and R⁴ are independently —H, halo, C₁-C₃ alkyl,—OR⁷ or —CN. In some such embodiments, w is 0. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and R¹, R², R³, and R⁴ areindependently —H, halo, C₁-C₃ alkyl, —OR⁷ or —CN. In some suchembodiments, two adjacent instances of R¹, R², R³, and R⁴ together form—O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and two adjacent instances of R¹,R², R³, and R⁴ together form —O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—.

In some embodiments, a provided compound is a compound of formula (Ic),or a pharmaceutically acceptable salt thereof, wherein each of m, n1,n2, n3, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, w, and Z is as described inembodiments for formula I, supra, or described in embodiments herein,both singly and in combination. In some such embodiments, Z is C. Insome such embodiments, Z is C, n2 is 0 and n3 is 0. In some suchembodiments, Z is C, and one of n2 and n3 is 0 and the other is 1. Insome such embodiments, Z is C, n2 is 1 and n3 is 1. In some suchembodiments, at least two of R¹, R², R³, and R⁴ are —H. In some suchembodiments, at least three of R¹, R², R³, and R⁴ are —H. In some suchembodiments, R^(a) is —H. In some such embodiments, R is —H. In somesuch embodiments, R^(a) is —H and R is —H. In some such embodiments,each instance of R⁵ is —F or —CH₃. In some such embodiments, R^(a) is—H, R is —H, and each instance of R⁵ is —F or —CH₃. In some suchembodiments, each instance of R⁶ is —F or —CH₃. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;and each instance of R⁶ is —F or —CH₃. In some such embodiments, eachinstance of R⁶ is —CH₃. In some such embodiments, R^(a) is —H; R is —H;each instance of R⁵ is —F or —CH₃; and each instance of R⁶ is —CH₃. Insome such embodiments, m is 0. In some such embodiments, R^(a) is —H; Ris —H; each instance of R⁵ is —F or —CH₃; each instance of R⁶ is —F or—CH₃; and m is 0. In some such embodiments, w is 0. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;each instance of R⁶ is —F or —CH₃; m is 0; and w is 0. In some suchembodiments, R¹, R², R³, and R⁴ are independently —H, halo, C₁-C₃ alkyl,—OR⁷ or —CN. In some such embodiments, w is 0. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and R¹, R², R³, and R⁴ areindependently —H, halo, C₁-C₃ alkyl, —OR⁷ or —CN. In some suchembodiments, two adjacent instances of R¹, R², R³, and R⁴ together form—O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and two adjacent instances of R¹,R², R³, and R⁴ together form —O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—.

In some embodiments, a provided compound is a compound of formula (Id),or a pharmaceutically acceptable salt thereof, wherein each of m, n1,n2, n3, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, w, and Z is as described inembodiments for formula I, supra, or described in embodiments herein,both singly and in combination. In some such embodiments, Z is C. Insome such embodiments, Z is C, n2 is 0 and n3 is 0. In some suchembodiments, Z is C, and one of n2 and n3 is 0 and the other is 1. Insome such embodiments, Z is C, n2 is 1 and n3 is 1. In some suchembodiments, at least two of R¹, R², R³, and R⁴ are —H. In some suchembodiments, at least three of R¹, R², R³, and R⁴ are —H. In some suchembodiments, R^(a) is —H. In some such embodiments, R is —H. In somesuch embodiments, R^(a) is —H and R is —H. In some such embodiments,each instance of R⁵ is —F or —CH₃. In some such embodiments, R^(a) is—H, R is —H, and each instance of R⁵ is —F or —CH₃. In some suchembodiments, each instance of R⁶ is —F or —CH₃. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;and each instance of R⁶ is —F or —CH₃. In some such embodiments, eachinstance of R⁶ is —CH₃. In some such embodiments, R^(a) is —H; R is —H;each instance of R⁵ is —F or —CH₃; and each instance of R⁶ is —CH₃. Insome such embodiments, m is 0. In some such embodiments, R^(a) is —H; Ris —H; each instance of R⁵ is —F or —CH₃; each instance of R⁶ is —F or—CH₃; and m is 0. In some such embodiments, w is 0. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;each instance of R⁶ is —F or —CH₃; m is 0; and w is 0. In some suchembodiments, R¹, R², R³, and R⁴ are independently —H, halo, C₁-C₃ alkyl,—OR⁷ or —CN. In some such embodiments, w is 0. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and R¹, R², R³, and R⁴ areindependently —H, halo, C₁-C₃ alkyl, —OR⁷ or —CN. In some suchembodiments, two adjacent instances of R¹, R², R³, and R⁴ together form—O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and two adjacent instances of R¹,R², R³, and R⁴ together form —O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—.

In some embodiments, a provided compound is a compound of formula (I-C):

or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R,R^(a), R¹, R², R³, R⁴, R⁵, R⁶, and w is as described in embodiments forformula I, supra, or described in embodiments herein, both singly and incombination.

In some embodiments, a provided compound is a compound of formula (I-C),or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R,R^(a), R¹, R², R³, R⁴, R⁵, R⁶, and w is as described in embodiments forformula I, supra, or described in embodiments herein, both singly and incombination. In some such embodiments, at least two of R¹, R², R³, andR⁴ are —H. In some such embodiments, at least three of R¹, R², R³, andR⁴ are —H. In some such embodiments, R^(a) is —H. In some suchembodiments, R is —H. In some such embodiments, R^(a) is —H and R is —H.In some such embodiments, each instance of R⁵ is —F or —CH₃. In somesuch embodiments, R^(a) is —H, R is —H, and each instance of R⁵ is —F or—CH₃. In some such embodiments, each instance of R⁶ is —F or —CH₃. Insome such embodiments, R^(a) is —H; R is —H; each instance of R⁵ is —For —CH₃; and each instance of R⁶ is —F or —CH₃. In some suchembodiments, each instance of R⁶ is —CH₃. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; and eachinstance of R⁶ is —CH₃. In some such embodiments, m is 0. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;each instance of R⁶ is —F or —CH₃; and m is 0. In some such embodiments,w is 0. In some such embodiments, R^(a) is —H; R is —H; each instance ofR⁵ is —F or —CH₃; each instance of R⁶ is —F or —CH₃; m is 0; and w is 0.In some such embodiments, R¹, R², R³, and R⁴ are independently —H, halo,C₁-C₃ alkyl, —OR⁷ or —CN. In some such embodiments, w is 0. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;each instance of R⁶ is —F or —CH₃; m is 0; w is 0; and R¹, R², R³, andR⁴ are independently —H, halo, C₁-C₃ alkyl, —OR⁷ or —CN. In some suchembodiments, two adjacent instances of R¹, R², R³, and R⁴ together form—O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and two adjacent instances of R¹,R², R³, and R⁴ together form —O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—.

In some embodiments, a provided compound is a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R,R^(a), R¹, R², R³, R⁴, R⁵, R⁶, and w is as described in embodiments forformula I, supra, or described in embodiments herein, both singly and incombination. In some such embodiments, at least two of R¹, R², R³, andR⁴ are —H. In some such embodiments, at least three of R¹, R², R³, andR⁴ are —H. In some such embodiments, R^(a) is —H. In some suchembodiments, R is —H. In some such embodiments, R^(a) is —H and R is —H.In some such embodiments, each instance of R⁵ is —F or —CH₃. In somesuch embodiments, R^(a) is —H, R is —H, and each instance of R⁵ is —F or—CH₃. In some such embodiments, each instance of R⁶ is —F or —CH₃. Insome such embodiments, R^(a) is —H; R is —H; each instance of R⁵ is —For —CH₃; and each instance of R⁶ is —F or —CH₃. In some suchembodiments, each instance of R⁶ is —CH₃. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; and eachinstance of R⁶ is —CH₃. In some such embodiments, m is 0. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;each instance of R⁶ is —F or —CH₃; and m is 0. In some such embodiments,w is 0. In some such embodiments, R^(a) is —H; R is —H; each instance ofR⁵ is —F or —CH₃; each instance of R⁶ is —F or —CH₃; m is 0; and w is 0.In some such embodiments, R¹, R², R³, and R⁴ are independently —H, halo,C₁-C₃ alkyl, —OR⁷ or —CN. In some such embodiments, w is 0. In some suchembodiments, R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃;each instance of R⁶ is —F or —CH₃; m is 0; w is 0; and R¹, R², R³, andR⁴ are independently —H, halo, C₁-C₃ alkyl, —OR⁷ or —CN. In some suchembodiments, two adjacent instances of R¹, R², R³, and R⁴ together form—O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—. In some such embodiments,R^(a) is —H; R is —H; each instance of R⁵ is —F or —CH₃; each instanceof R⁶ is —F or —CH₃; m is 0; w is 0; and two adjacent instances of R¹,R², R³, and R⁴ together form —O—CH₂—O—, —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—.

In some embodiments, a provided compound is a compound of formula (IIa),(IIb), (IIc), or (IId):

or a pharmaceutically acceptable salt thereof, with the proviso asdescribed in embodiments for formula I, wherein each of m, n1, R, R^(a),R¹, R², R³, R⁴, R⁵, R⁶, and w is as described in embodiments for formulaI, supra, or described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula I, or a pharmaceutically acceptable salt thereof, wherein thecompound of formula I is a compound of formula III:

wherein each of m, n1, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, and w is asdescribed in embodiments for formula I, supra, or described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I selected from formulas (IIIa), (IIIb), (IIIc), and (IIId):

or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R,R^(a), R¹, R², R³, R⁴, R⁵, R⁶, and w is as described in embodiments forformula I, supra, or described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula I, or a pharmaceutically acceptable salt thereof, wherein thecompound of formula I is a compound of formula IV:

wherein each of m, n1, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, and w is asdescribed in embodiments for formula I, supra, or described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I selected from formulas (IVa), (IVb), (IVc), and (IVd):

or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R,R^(a), R¹, R², R³, R⁴, R⁵, R⁶, and w is as described in embodiments forformula I, supra, or described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula I, or a pharmaceutically acceptable salt thereof, wherein thecompound of formula I is a compound of formula V:

wherein each of m, n1, R, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, and w is asdescribed in embodiments for formula I, supra, or described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I selected from formulas (Va), (Vb), (Vc), and (Vd):

or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R,R^(a), R¹, R², R³, R⁴, R⁵, R⁶, and w is as described in embodiments forformula I, supra, or described in embodiments herein, both singly and incombination.

Exemplary compounds of formula I are set forth in Table 1, below.

TABLE 1

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

In some embodiments, the present invention provides a compound selectedfrom those depicted in Table 1, above, or a pharmaceutically acceptablesalt thereof.

Schemes below provide exemplary synthetic methods for the preparation ofthe compounds provided herein. One skilled in the art will understandthat suitable adjustments to reagents, protecting groups, reactionconditions, and reaction sequences may be employed to prepare thecompounds provided herein.

The compounds of formula (I) may be prepared following Schemes A-D,using suitable starting materials known in the art and/or available froma commercial source. The starting materials of Schemes A-D may beprepared from commercially available compounds using procedures andconditions known in the art.

As shown in Scheme A, a suitable hydroxyalkyl substituted benzene (1-1)is reacted with a suitable N-protected aminoaldehyde (1-2) in thepresence of an acid or a Lewis acid such as trifluoromethanesulfonicacid or trimethylsilyl trifluoromethanesulfonate to afford a cyclizedproduct (1-3), which can be deprotected to afford a compound of formula(I). Chiral HPLC may be used to separate the enantiomers of a compoundof formula (I).

As shown in Scheme B, a suitable O-protected1-hydroxyalkyl-2-bromo-benzene (2-1) is treated with a lithium orGrignard reagent. The anion formed is reacted with a suitableN-protected aminoketone (2-2), followed by O-deprotection with asuitable deprotecting reagent to afford a diol (2-3). Cyclization of thediol (2-3) to a cyclized product (2-4) is achieved under variousconditions (for example, MsCl/Et₃N followed by t-BuOK treatment; TMSOTftreatment, etc.). The cyclized product (2-4) can be N-deprotected toafford a compound of formula (I). Chiral HPLC may be used to separatethe enantiomers of a compound of formula (I).

As shown in Scheme C, a suitable bromo- or OTf-substituted N-protectedcyclized product (3-1) is converted to the corresponding CN, aryl orheteroaryl substituted product (3-2) under various organometalliccross-coupling conditions known in the art. The cyclized product (3-2)can be N-deprotected to afford a compound of formula (I). Chiral HPLCmay be used to separate the enantiomers of a compound of formula (I).

As shown in Scheme D, a suitable N-unsubstituted product (4-1) isalkylated under any reductive amination condition known in the art toafford the corresponding compound of formula (I).

4. Uses, Formulation and Administration and Pharmaceutically AcceptableCompositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention, or a pharmaceuticallyacceptable salt, ester, or salt of ester thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle. In some embodiments, theamount of compound in compositions of this invention is such that iseffective to treat, prevent, and/or manage various neurological and/orpsychiatric disorders and/or symptoms in a patient. In some embodiments,a composition of this invention is formulated for administration to apatient in need of such composition. In some embodiments, a compositionof this invention is formulated for oral administration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an active metabolite or residue thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including capsules,tablets, aqueous suspensions or solutions. In the case of tablets fororal use, carriers commonly used include lactose and corn starch.Lubricating agents, such as magnesium stearate, are also typicallyadded. For oral administration in a capsule form, useful diluentsinclude lactose and dried cornstarch. When aqueous suspensions arerequired for oral use, the active ingredient may be combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater.

Alternatively, provided pharmaceutically acceptable compositions can beformulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon a variety of factors, including the hosttreated and the particular mode of administration. Preferably, providedcompositions should be formulated so that a dosage of between 0.01-100mg/kg body weight/day of a compound of the present invention can beadministered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

5. Uses of Compounds and Pharmaceutically Acceptable Compositions

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating a neurological or psychiatricdisorder.

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating a neurologicaland/or psychiatric disorder in a patient.

In some embodiments, the neurological or psychiatric disorder isselected from a psychosis, including schizophrenia (paranoid,disorganized, catatonic or undifferentiated), schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,shared psychotic disorder, psychotic disorder due to a general medicalcondition and substance-induced or drug-induced (phencyclidine, ketamineand other dissociative anesthetics, amphetamine and otherpsychostimulants and cocaine) psychosispsychotic disorder, psychosisassociated with affective disorders, brief reactive psychosis,schizoaffective psychosis, “schizophrenia-spectrum” disorders such asschizoid or schizotypal personality disorders, or illness associatedwith psychosis (such as major depression, manic depressive (bipolar)disorder, Alzheimer's disease and post-traumatic stress syndrome),including both positive, negative, and cognitive symptoms ofschizophrenia and other psychoses; cognitive disorders includingdementia (associated with Alzheimer's disease, ischemia, multi-infarctdementia, trauma, vascular problems or stroke, HIV disease, Parkinson'sdisease, Huntington's disease, Down syndrome, Pick's disease,Creutzfeldt-Jacob disease, perinatal hypoxia, other general medicalconditions or substance abuse); delirium, amnestic disorders or agerelated cognitive decline; anxiety disorders including acute stressdisorder, agoraphobia, generalized anxiety disorder,obsessive-compulsive disorder, panic attack, panic disorder,post-traumatic stress disorder, separation anxiety disorder, socialphobia, specific phobia, substance-induced anxiety disorder and anxietydue to a general medical condition; substance-related disorders andaddictive behaviors (including substance-induced delirium, persistingdementia, persisting amnestic disorder, psychotic disorder or anxietydisorder; tolerance, dependence or withdrawal from substances includingalcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants,nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics);obesity, bulimia nervosa and compulsive eating disorders; bipolardisorders, mood disorders including depressive disorders; depressionincluding unipolar depression, seasonal depression and post-partumdepression, premenstrual syndrome (PMS) and premenstrual dysphoricdisorder (PDD), mood disorders due to a general medical condition, andsubstance-induced mood disorders; learning disorders, pervasivedevelopmental disorder including autistic disorder, attention disordersincluding attention-deficit hyperactivity disorder (ADHD) and conductdisorder; disorders such as autism, depression, benign forgetfulness,childhood learning disorders and closed head injury; movement disorders,including akinesias and akinetic-rigid syndromes (including Parkinson'sdisease, drug-induced parkinsonism, postencephalitic parkinsonism,progressive supranuclear palsy, multiple system atrophy, corticobasaldegeneration, Parkinsonism-ALS dementia complex and basal gangliacalcification), medication-induced Parkinsonism (such asneuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Gilles de la Tourette's syndrome, epilepsy, muscular spasms anddisorders associated with muscular spasticity or weakness includingtremors; dyskinesias {including drug e.g. L-DOPA induced dyskinesiatremor (such as rest tremor, postural tremor, intention tremor), chorea(such as Sydenham's chorea, Huntington's disease, benign hereditarychorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea andhemiballism), myoclonus (including generalised myoclonus and focalmyoclonus), tics (including simple tics, complex tics and symptomatictics), and dystonia (including generalised dystonia such as iodiopathicdystonia, drug-induced dystonia, symptomatic dystonia and paroxymaldystonia, and focal dystonia such as blepharospasm, oromandibulardystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia,dystonic writer's cramp and hemiplegic dystonia)}; urinary incontinence;neuronal damage including ocular damage, retinopathy or maculardegeneration of the eye, tinnitus, hearing impairment and loss, andbrain edema; emesis; and sleep disorders including insomnia andnarcolepsy.

In some embodiments, the neurological or psychiatric disorder isAlzheimer's Disease, Parkinson's Disease, depression, cognitiveimpairment, stroke, schizophrenia, Down Syndrome, or Fetal AlcoholSyndrome. In some embodiments, the neurological or psychiatric disorderis Alzheimer's Disease. In some embodiments, the neurological orpsychiatric disorder is Parkinson's Disease. In some embodiments, theneurological or psychiatric disorder is depression. In some embodiments,the neurological or psychiatric disorder is cognitive impairment. Insome embodiments, the cognitive impairment is cognitive dysfunctionassociated with depression, for example, major depressive disorder. Insome embodiments, the neurological or psychiatric disorder is stroke. Insome embodiments, the neurological or psychiatric disorder isschizophrenia. In some embodiments, the neurological or psychiatricdisorder is Down Syndrome. In some embodiments, the neurological orpsychiatric disorder is Fetal Alcohol Syndrome.

In some embodiments, the neurological or psychiatric disorder involves adeficit in cognition (cognitive domains as defined by the DSM-5 are:complex attention, executive function, learning and memory, language,perceptual-motor, social cognition). In some embodiments, theneurological or psychiatric disorder is associated with a deficit indopamine signaling. In some embodiments, the neurological or psychiatricdisorder is associated with basal ganglia dysfunction. In someembodiments, the neurological or psychiatric disorder is associated withdysregulated locomotor activity. In some embodiments, the neurologicalor psychiatric disorder is associated with impairment of prefrontalcortex functioning.

In some embodiments, the present invention provides a method of treatingone or more symptoms of a neurological and/or psychiatric disorderprovided herein. Such disorders include mood disorders, includingbipolar I disorder, bipolar II disorder, bipolar depression, mania,cyclothymic disorder, substance/medication-induced bipolar and relateddisorders, bipolar and related disorder due to another medicalcondition, other specified bipolar and related disorder, and unspecifiedbipolar and related disorders; psychotic disorders, includingschizophrenia, schizophrenia spectrum disorder, acute schizophrenia,chronic schizophrenia, NOS schizophrenia, schizoid personality disorder,schizotypal personality disorder, delusional disorder, psychosis,psychotic disorder, brief psychotic disorder, shared psychotic disorder,psychotic disorder due to a general medical condition, drug-inducedpsychosis (e.g., cocaine, alcohol, amphetamine), schizoaffectivedisorder, aggression, delirium, Parkinson's psychosis, excitativepsychosis, Tourette's syndrome, and organic or NOS psychosis; depressivedisorders, including disruptive mood dysregulation disorder, majordepressive disorder (MDD) (including major depressive episode),dysthymia, persistent depressive disorder (dysthymia), treatmentresistant depression, premenstrual dysphoric disorder,substance/medication-induced depressive disorder, depressive disorderdue to another medical condition, other specified depressive disorder,and unspecified depressive disorder; anxiety disorders, includingseparation anxiety disorder, selective mutism, specific phobia, socialanxiety disorder (social phobia), panic disorder, panic attackspecifier, agoraphobia, generalized anxiety disorder,substance/medication-induced anxiety disorder, anxiety disorder due toanother medical condition, other specified anxiety disorder, andunspecified anxiety disorder; stressor-related disorders, includingreactive attachment disorder, disinhibited social engagement disorder,posttraumatic stress disorder (PTSD), acute stress disorder, andadjustment disorders; and other disorders including substance abuse ordependency (e.g., nicotine, alcohol, cocaine), addiction, eatingdisorders, behavior disorder, seizure, vertigo, epilepsy, agitation,aggression, neurodegenerative disease, Alzheimer's disease, Parkinson'sdisease, dyskinesias, Huntington's disease, dementia, premenstrualdysphoria; and attention deficit disorder (ADD) and neurodevelopmentaldisorders, including attention deficit hyperactivity disorder (ADHD)),autism, autism spectrum disorder, obsessive-compulsive disorder, pain(e.g., neuropathic pain, sensitization accompanying neuropathic pain,and inflammatory pain), fibromyalgia, migraine, cognitive impairment,movement disorder, restless leg syndrome (RLS), multiple sclerosis,Parkinson's disease, Huntington's disease, dyskinesias multiplesclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytimesleepiness, jet lag, drowsy side effect of medications, insomnia, sexualdysfunction, hypertension, emesis, Lesche-Nyhane disease, Wilson'sdisease, and Huntington's chorea. In some embodiments, the neurologicaland/or psychiatric disorders include agitation and aggression. In someembodiments, the agitation and aggression are associated withAlzheimer's Disease, Parkinson's Disease, and/or autism. In someembodiments, the neurological and/or psychiatric disorders areobsessive-compulsive disorder and related disorders (e.g., bodydysmorphic disorder, hoarding disorder, trichotillomania, excoriationdisorder). In some embodiments, the neurological and/or psychiatricdisorders are disruptive, impulse-control, and conduct disordersincluding oppositional defiant disorder, intermittent explosivedisorder, conduct disorder, antisocial personality disorder, pyromania,kleptomania, other specified disruptive, impulse-control, and conductdisorder, unspecified disruptive, impulse-control, and conduct disorder.

In some embodiments, the present invention provides a method of treatingone or more symptoms including depression (e.g., major depressivedisorder or dysthymia); bipolar disorder, seasonal affective disorder;cognitive deficit; sleep related disorder (e.g., sleep apnea, insomnia,narcolepsy, cataplexy) including those sleep disorders which areproduced by psychiatric conditions; chronic fatigue syndrome; anxieties(e.g., general anxiety disorder, social anxiety disorder, panicdisorder); obsessive compulsive disorder; post-menopausal vasomotorsymptoms (e.g., hot flashes, night sweats); neurodegenerative disease(e.g., Parkinson's disease, Alzheimer's disease and amyotrophic lateralsclerosis); manic disorder; dysthymic disorder; and obesity.

In some embodiments, a depressive disorder is associated with acutesuicidality or suicide ideation. The United States Food and DrugAdministration has adopted a “black box” label warning indicating thatantidepressants may increase the risk of suicidal thinking and behaviorin some children, adolescents and young adults (up to age 24) with adepressive disorder such as MDD. In some embodiments, a providedcompound does not increase the risk of suicidal thinking and/or behaviorin children, adolescents and/or young adults with a depressive disorder,e.g., with MDD. In some embodiments, the present invention provides amethod of treating one or more symptoms of a depressive disorder (e.g.,MDD) in children, adolescents and/or young adults without increasing therisk of suicidal thinking and/or behavior.

In some embodiments, the present invention provides a method of treatingone or more symptoms including senile dementia, Alzheimer's typedementia, cognition, memory loss, amnesia/amnestic syndrome,disturbances of consciousness, coma, lowering of attention, speechdisorder, Lennox syndrome, and hyperkinetic syndrome.

In some embodiments, the present invention provides a method of treatingone or more symptoms of neuropathic pain, including post herpetic (orpost-shingles) neuralgia, reflex sympathetic dystrophy/causalgia ornerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheralneuropathy (such as diabetic neuropathy or neuropathy arising fromchronic alcohol use).

In some embodiments, the present invention provides a method of treatingone or more symptoms including obesity; migraine or migraine headache;and sexual dysfunction, in men or women, including without limitationsexual dysfunction caused by psychological and/or physiological factors,erectile dysfunction, premature ejaculation, vaginal dryness, lack ofsexual excitement, inability to obtain orgasm, and psycho-sexualdysfunction, including without limitation, inhibited sexual desire,inhibited sexual excitement, inhibited female orgasm, inhibited maleorgasm, functional dyspareunia, functional vaginismus, and atypicalpsychosexual dysfunction.

In some embodiments, the present invention provides a method ofsuppressing rapid eye movement (REM) during both sleep and daytimeequivalent.

In some embodiments, the present invention provides a method ofsuppressing or eliminating pathological or excessive REM during thenight or daytime equivalent.

In some embodiments, the present invention provides a method of treatingone or more symptoms including cataplexy (sudden involuntary transientbouts of muscle weakness or paralysis while awake); nighttime sleepdisturbance/sleep fragmentation associated with narcolepsy or otherconditions; sleep paralysis associated with narcolepsy or otherconditions; hypnagogic and hypnapompic hallucinations associated withnarcolepsy or other conditions; and excessive daytime sleepinessassociated with narcolepsy, sleep apnea or shift work disorder and othermedical conditions such as cancer, chronic fatigue syndrome andfibromyalgia.

In some embodiments, the present invention provides a method of treatinga neurological and/or psychiatric disorder described herein, comprisingadministering a compound of the invention in conjunction with one ormore pharmaceutical agents. Suitable pharmaceutical agents that may beused in combination with the compounds of the present invention includeanti-Parkinson's drugs, anti-Alzheimer's drugs, anti-depressants,anti-psychotics, mood stabilizers, anti-ischemics, CNS depressants,anti-cholinergics, and nootropics. In some embodiments, suitablepharmaceutical agents are anxiolytics.

Suitable anti-Parkinson's drugs include dopamine replacement therapy(e.g. L-DOPA, carbidopa, COMT inhibitors such as entacapone), dopamineagonists (e.g. D1 agonists, D2 agonists, mixed D1/D2 agonists;bromocriptine, pergolide, cabergoline, ropinirole, pramipexole, orapomorphine in combination with domperidone), histamine H2 antagonists,and monoamine oxidase inhibitors such as selegiline and tranylcypromine.

In some embodiments, compounds of the invention can be used incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl(benzhexyl)hydrochloride, COMTinhibitors such as entacapone, MAO A/B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.Lisuride and pramipexole are commonly used in a non-salt form.

Suitable anti-Alzheimer's drugs include beta-secretase inhibitors,gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID'sincluding ibuprofen, vitamin E, and anti-amyloid antibodies. In someembodiments, an anti-Alzheimer's drug is memantine.

Suitable anti-depressants and anti-anxiety agents include norepinephrinereuptake inhibitors (including tertiary amine tricyclics and secondaryamine tricyclics), selective serotonin reuptake inhibitors (SSRIs),monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamineoxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors(SNRIs), serotonin, norepinephrine and dopamine reuptake inhibitors,corticotropin releasing factor (CRF) antagonists, α-adrenoreceptorantagonists, neurokinin-1 receptor antagonists, atypicalanti-depressants, benzodiazepines, 5-HT1A agonists or antagonists,especially 5-HT1A partial agonists, and corticotropin releasing factor(CRF) antagonists.

Specific suitable anti-depressant and anti-anxiety agents includeamitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, citalopram, escitalopram, maprotiline,nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine andsertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline;moclobemide: venlafaxine; desvenlafaxine; duloxetine; aprepitant;bupropion, mirtazapine, vilazodone, lithium, nefazodone, trazodone andviloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate,diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone,flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptablesalts thereof. In some embodiments, suitable anti-depressant andanti-anxiety agents are tianeptine, or pharmaceutically acceptable saltsthereof.

Suitable anti-psychotic and mood stabilizer agents include D2antagonists, 5HT2A antagonists, atypical antipsychotics, lithium, andanticonvulsants.

Specific suitable anti-psychotic and mood stabilizer agents includechlorpromazine, fluphenazine, haloperidol, amisulpride, chlorpromazine,perphenazine, thioridazine, trifluoperazine, aripiprazole, asenapine,clozapine, olanzapine, paliperidone, quetiapine, risperidone,ziprasidone, lurasidone, flupentixol, levomepromazine, pericyazine,perphenazine, pimozide, prochlorperazine, zuclopenthixol, olanzapine andfluoxetine, lithium, carbamazepine, lamotrigine, valproic acid andpharmaceutically acceptable salts thereof.

In some embodiments, compounds of the invention may be used incombination with other therapies. Suitable therapies includepsychotherapy, cognitive behavioral therapy, electroconvulsive therapy,transcranial magnetic stimulation, vagus nerve stimulation, anddeep-brain stimulation.

The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. The compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Insome embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

In some embodiments, a combination of 2 or more therapeutic agents maybe administered together with the compounds of the invention. In someembodiments, a combination of 3 or more therapeutic agents may beadministered with the compounds of the invention.

Other examples of agents the compounds of this invention may also becombined with include: vitamins and nutritional supplements, antiemetics(e.g. 5-HT3 receptor antagonists, dopamine antagonists, NK1 receptorantagonists, histamine receptor antagonists, cannabinoids,benzodiazepines, or anticholinergics), agents for treating MultipleSclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®),Copaxone®, and mitoxantrone; treatments for asthma such as albuterol andSingulair®; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins, fibrates, cholesterolabsorption inhibitors, bile acid sequestrants, and niacin; agents fortreating liver disease such as corticosteroids, cholestyramine,interferons, and anti-viral agents; agents for treating blood disorderssuch as corticosteroids, anti-leukemic agents, and growth factors;agents for treating immunodeficiency disorders such as gamma globulin;and anti-diabetic agents such as biguanides (metformin, phenformin,buformin), thiazolidinediones (rosiglitazone, pioglitazone,troglitazone), sulfonylureas (tolbutamide, acetohexamide, tolazamide,chlorpropamide, glipizide, glyburide, glimepiride, gliclazide),meglitinides (repaglinide, nateglinide), alpha-glucosidase inhibitors(miglitol, acarbose), incretin mimetics (exenatide, liraglutide,taspoglutide), gastric inhibitory peptide analogs, DPP-4 inhibitors(vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin),amylin analogs (pramlintide), and insulin and insulin analogs.

In some embodiments, a compound of the present invention, or apharmaceutically acceptable salt thereof, is administered in combinationwith an antisense agent, a monoclonal or polyclonal antibody, or ansiRNA therapeutic.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another, normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of formula I,or a pharmaceutically acceptable salt thereof, an additional therapeuticagent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

The amount of both, an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions may be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-100 mg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

In some embodiments, the present invention provides a medicamentcomprising at least one compound of formula I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,adjuvant, or vehicle.

In some embodiments, the present invention provides the use of acompound of formula I, or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for the treatment of a neurologicaland/or psychiatric disorder.

EXAMPLES

As depicted in the Examples below, in some embodiments, compounds areprepared according to the following procedures. It will be appreciatedthat, although the general methods depict the synthesis of certaincompounds of the present invention, the following methods, and othermethods known to one of ordinary skill in the art, can be applied to allcompounds and subclasses and species of each of these compounds, asdescribed herein.

In the examples below, unless otherwise indicated, all temperatures areset forth in degrees Celsius and all parts and percentages are byweight. Reagents were purchased from commercial suppliers, such asSigma-Aldrich Chemical Company, and were used without furtherpurification unless otherwise indicated. Reagents were preparedfollowing standard literature procedures known to those skilled in theart. All solvents requiring purification or drying were treated usingstandard methods known to those skilled in the art, unless otherwiseindicated.

The reactions set forth below were done generally at ambienttemperature, unless otherwise indicated. The reaction flasks were fittedwith rubber septa for introduction of substrates and reagents viasyringe. Analytical thin layer chromatography (TLC) was performed usingglass-backed silica gel pre-coated plates (Merck Art 5719) and elutedwith appropriate solvent ratios (v/v). Reactions were assayed by TLC orLCMS, and terminated as judged by the consumption of starting material.Visualization of the TLC plates was done with UV light (254 wavelength)or with an appropriate TLC visualizing solvent, such as basic aqueousKMnO₄ solution activated with heat. Flash column chromatography (See,e.g., Still et al., J. Org. Chem., 43: 2923 (1978)) was performed usingsilica gel 60 (Merck Art 9385) or various MPLC systems.

The compound structures in the examples below were confirmed by one ormore of the following methods: proton magnetic resonance spectroscopy,mass spectroscopy, and melting point. Proton magnetic resonance (¹H NMR)spectra were determined using an NMR spectrometer operating at 400 MHzfield strength. Chemical shifts are reported in the form of delta (6)values given in parts per million (ppm) relative to an internalstandard, such as tetramethylsilane (TMS). Alternatively, ¹H NMR spectrawere referenced to signals from residual protons in deuterated solventsas follows: CDCl₃=7.25 ppm; DMSO-d₆=2.49 ppm; C₆D₆=7.16 ppm; CD₃OD=3.30ppm. Peak multiplicities are designated as follows: s, singlet; d,doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets;q, quartet; quint, quintet; sept, septet; br, broadened; and m,multiplet. Coupling constants are given in Hertz (Hz). Mass spectra (MS)data were obtained using a mass spectrometer with APCI or ESIionization.

As used herein, and unless otherwise specified, “Me” means methyl, “Et”means ethyl, “Ac” means acetyl, “BINAP” means2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, “Dess-Martin reagent” means1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, “DCM”means dichloromethane, “DIEA” means diisopropylethylamine, “DMF” meansdimethylformamide, “EDCl” meansN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, “EtOAc”means ethyl acetate, “EtOH” means ethanol, “HATU” meansO-(7-azabenzotriazol-1-yl)-N, N, N′, N′-tetramethyluroniumhexafluorophosphate, “HOBt” means hydroxybenzotriazole, “m-CPBA” means3-chloro-perbenzoic acid, “MeCN” means acetonitrile, “MeOH” meansmethanol, “PE” means petroleum ether, “RT” or “rt” means roomtemperature, “t-BuOH” means tert-butanol, “t-BuONa” means sodiumtert-butoxide, “TBDMSCl” means tert-butyldimethylsilyl chloride, “TEA”means triethylamine, “THF” means tetrahydrofuran, “TMSI” meansiodotrimethylsilane, “Xantphos” means4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, “h” or “hr” meanshour(s), “min” means minute(s), “cat.” means catalytic, “aq” meansaqueous, and “TFA” means trifluoroacetic acid.

Example 1. Preparation of Compounds Example 1.1. Procedure A. CertainProvided Compounds were Made Following a Procedure Exemplified byExample 1.1.1 Example 1.1.1. (S)-2-((S)-isochroman-1-yl)pyrrolidine(I-17) and (S)-2-((R)-isochroman-1-yl)pyrrolidine (I-18)

(a). (2S)-2-(isochroman-1-yl)pyrrolidine

To a mixture of 2-phenylethanol (2 g, 16.38 mmol) and (S)-tert-butyl2-formylpyrrolidine-1-carboxylate (6.52 g, 32.76 mmol) was addedtrifluoromethanesulphonic acid (3 mL) at 0° C. slowly. After thereaction was stirred at room temperature for 2 h, ice-water (50 mL) wasadded. The mixture was extracted with dichloromethane/MeOH (10:1, 50mL×3). The organic layers were combined, dried and concentrated to givethe crude product (2.65 g) as brown oil. ESI: m/z=204[M+H].

(b). (2S)-tert-butyl 2-(isochroman-1-yl) pyrrolidine-1-carboxylate

To crude (2S)-2-(isochroman-1-yl) pyrrolidine (2.65 g, 13 mmol) obtainedabove was added water (50 mL), sodium hydroxide (1 g, 26 mmol), and thendi-tert-butyl dicarbonate (5.69 g, 26 mmol). The mixture was stirred atroom temperature for 1 h. The mixture was extracted with EtOAc (30mL×3), and the organic layers were combined, dried and concentrated. Thecrude was purified by reverse gel column chromatography (eluted withwater/CH₃CN=100:65, 0.01% NH₄OH) to give the desired compound (3.65 g asa colorless oil).

(c). TFA Salt of (2S)-2-(isochroman-1-yl) pyrrolidine

To a solution of TFA (5 mL) in methylene chloride (20 mL) was added(2S)-tert-butyl 2-(isochroman-1-yl) pyrrolidine-1-carboxylate (3.65 g,12 mmol). The mixture was stirred at room temperature for 3 h and thesolvent was removed to yield the crude product 2.3 g, as colorless oil.MS (ESI): m/z=204[M+H]⁺.

(d). (S)-2-((S)-isochroman-1-yl) pyrrolidine and(S)-2-((R)-isochroman-1-yl) pyrrolidine

The mixture from previous step (1.95 g, 9.6 mmol) was purified andseparated by prep. HPLC in 0.01% aqueous TFA to give the twodiastereoisomers, which were separately further purified by chiral HPLCusing Column: AY-H (250*4.6 mm 5 μm) and Mobile Phase: n-Hexane (0.1%DEA):EtOH (0.1% DEA)=90:10 to give(S)-2-((S)-isochroman-1-yl)pyrrolidine (86 mg yellow oil, R.T.: 7.042min, ee %: 98%) and (S)-2-((R)-6-fluoroisochroman-1-yl) pyrrolidine (360mg yellow oil, R.T.: 7.408 min, ee %: 100%).

¹HNMR of (S)-2-((S)-isochroman-1-yl)pyrrolidine (I-17) (400 MHz, CDCl₃)δ 7.26˜7.11 (m, 4H), 4.78 (d, J=3.2 Hz, 1H), 4.24˜4.20 (m, 1H),3.79˜3.76 (td, J₁=10.8, J₂=3.5 Hz, 1H), 3.59˜3.57 (td, J₁=7.5, J₂=3.9Hz, 1H), 3.11˜2.98 (m, 2H), 2.79˜2.76 (m, 1H), 2.69˜2.65 (m, 1H), 2.28(s, 1H), 1.96˜1.73 (m, 4H).

¹HNMR of (S)-2-((R)-isochroman-1-yl)pyrrolidine (I-18) (400 MHz, CDCl₃)δ 7.19˜7.12 (m, 4H), 5.00 (d, J=2.5 Hz, 1H), 4.23˜4.18 (m, 1H),3.78˜3.72 (td, J₁=11.3, J₁=3.0 Hz, 1H), 3.59˜3.57 (td, J₁=7.9, J₁=3.5Hz, 1H), 3.22˜2.99 (m, 2H), 2.86˜2.81 (m, 1H), 2.63˜2.61 (m, 1H), 2.27(s, 1H), 1.71˜1.66 (m, 2H), 1.50˜1.44 (m, 2H).

Example 1.1.2. (R)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine (I-16) and(R)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine (I-15)

(R)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine (I-16) and(R)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine (I-15) were preparedusing a procedure analogous to that described in Example 1.1.1, butusing 2-(2-fluoro-phenyl)-ethanol in place of 2-phenylethanol and(R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine (I-16): MS (ESI): m/z 222(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.10 (m, 1H), 6.97 (d, J=7.8 Hz,1H), 6.89 (t, J=8.7 Hz, 1H), 4.94 (s, 1H), 4.23 (ddd, J=11.3, 5.8, 1.9Hz, 1H), 3.69 (td, J=11.1, 3.7 Hz, 1H), 3.57 (td, J=7.9, 3.5 Hz, 1H),3.19-3.06 (m, 1H), 2.91-2.68 (m, 3H), 1.76-1.62 (m, 2H), 1.53-1.37 (m,2H).

(R)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine (I-15): MS (ESI): m/z 222(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.10 (m, 1H), 7.05 (d, J=7.8 Hz,1H), 6.89 (t, J=8.7 Hz, 1H), 4.72 (d, J=3.2 Hz, 1H), 4.24 (ddd, J=11.3,5.8, 2.9 Hz, 1H), 3.73 (ddd, J=11.2, 10.3, 4.0 Hz, 1H), 3.58 (td, J=7.5,3.8 Hz, 1H), 3.03 (ddd, J=10.3, 6.9, 5.4 Hz, 1H), 2.87 (ddd, J=16.1,10.1, 5.8 Hz, 1H), 2.76 (dt, J=10.4, 7.5 Hz, 2H), 1.90 (dd, J=11.6, 4.2Hz, 2H), 1.84-1.71 (m, 2H).

Example 1.1.3. (S)-2-((S)-isochroman-1-yl)azetidine (I-79) and(S)-2-((R)-iso-chroman-1-yl)azetidine (I-80)

(S)-2-((S)-isochroman-1-yl)azetidine (I-79) and(S)-2-((R)-iso-chroman-1-yl)azetidine (I-80) were prepared using aprocedure analogous to that described in Example 1.1.1, but using(S)-tert-butyl 2-formylazetidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(S)-2-((S)-isochroman-1-yl)azetidine (I-79): MS (ESI): m/z 190 [M+H]⁺,¹HNMR (400 MHz, CDCL3): δ 7.10-7.21 (m, 4H), 4.73-4.74 (d, J=6.0 Hz,1H), 4.18-4.26 (m, 2H), 3.78-3.85 (dt, J₁=3.6 Hz, J₂=10.0 Hz, 1H),3.59-3.65 (q, J=7.6 Hz, 1H), 3.42-3.47 (m, 1H), 3.00-3.06 (m, 1H),2.55-2.74 (m, 2H), 2.35-2.43 (m, 1H), 2.11 (br, 1H).

(S)-2-((R)-iso-chroman-1-yl)azetidine (I-80): MS (ESI): m/z 190 [M+H]⁺,¹HNMR (400 MHz, MeOD): δ 7.20-7.271 (m, 3H), 7.10-7.12 (m, 1H),5.10-5.14 (m, 2H), 4.39-4.44 (m, 1H), 3.85-4.05 (m, 3H), 3.14-3.23 (m,1H), 2.72-2.76 (m, 1H), 2.21-39 (m, 2H).

Example 1.1.4. (S)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-94) and(S)-2-((R)-5-fluoroisochroman-1-yl)azetidine (I-93)

(S)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-94) and(S)-2-((R)-5-fluoroisochroman-1-yl)azetidine (I-93) were prepared usinga procedure analogous to that described in Example 1.1.1, but using2-(2-fluorophenyl)ethanol in place of 2-phenylethanol and (S)-tert-butyl2-formylazetidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(S)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-94): MS (ESI): m/z 208[M+H]⁺, ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.27-7.33 (m, 1H), 7.04-7.08(m, 2H), 5.13-5.18 (dt, J₁=3.6 Hz, J₂=8.4 Hz, 1H), 5.02 (s, 1H),4.39-4.44 (m, 1H), 4.04-4.11 (q, J=8.8 Hz, 1H), 3.81-3.91 (m, 2H),2.94-3.08 (m, 2H), 2.79-2.93 (m, 1H), 2.51-2.66 (m, 1H).

(S)-2-((R)-5-fluoroisochroman-1-yl)azetidine (I-93): MS (ESI): m/z 208[M+H]⁺, ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.24-7.29 (m, 1H), 7.02-7.06(t, J=8.8 Hz, 1H), 6.94-6.96 (d, J=7.6 Hz, 1H), 5.13-5.16 (m, 2H),4.44-4.49 (m, 1H), 3.83-4.04 (m, 3H), 2.95-3.03 (m, 1H), 2.83-2.88 (m,1H), 2.10-2.36 (m, 2H).

Example 1.1.5. (S)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-89) and(S)-2-((R)-6-fluoroisochroman-1-yl)azetidine (I-90)

(S)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-89) and(S)-2-((R)-6-fluoroisochroman-1-yl)azetidine (I-90) were prepared usinga procedure analogous to that described in Example 1.1.1, but using2-(3-fluorophenyl) ethanol in place of 2-phenylethanol and(S)-tert-butyl 2-formylazetidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(S)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-89): MS (ESI) m/z 208(M+H)⁺ ¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.13 (m, 1H), 6.90 (m, 2H),4.69 (d, J=6.0 Hz, 1H), 4.28 (m, 1H), 4.19 (m, 1H), 3.77 (m, 1H), 3.58(m, 1H), 3.37 (m, 1H), 3.05 (m, 1H), 2.72 (m, 2H), 2.38 (m, 1H).

(S)-2-((R)-6-fluoroisochroman-1-yl)azetidine (I-90): MS (ESI) m/z 208(M+H)⁺ ¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.17-7.14 (m, 1H), 7.01-6.99(m, 2H), 5.10-5.12 (m, 2H), 4.39-4.44 (m, 1H), 3.98-4.03 (m, 1H),3.92-3.85 (m, 2H), 3.18 (m, 1H), 2.78-2.79 (m, 1H), 2.30-2.34 (m, 2H).

Example 1.1.6. (S)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-85) and(S)-2-((R)-7-fluoroisochroman-1-yl)azetidine (I-86)

(S)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-85) and(S)-2-((R)-7-fluoroisochroman-1-yl)azetidine (I-86) were prepared usinga procedure analogous to that described in Example 1.1.1, but using2-(4-fluorophenyl)ethanol in place of 2-phenylethanol and (S)-tert-butyl2-formylazetidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(S)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-85): MS (ESI) m/z 208(M+H)⁺, ¹H NMR (400 MHz, MeOD) δ 7.26 (m, 1H), 7.03 (m, 2H), 5.11 (m,1H), 4.98 (m, 1H), 4.36 (m, 1H), 4.08 (m, 1H), 3.87 (m, 2H), 3.16 (m,1H), 2.98 (m, 1H), 2.73 (m, 1H), 2.61 (m, 1H).

(S)-2-((R)-7-fluoroisochroman-1-yl)azetidine (I-86): MS (ESI) m/z 208(M+H)⁺, ¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.15 (m, 1H), 6.93 (m, 2H),4.73 (d, J=5.2 Hz, 1H), 4.30 (m, 1H), 4.23 (m, 1H), 3.74 (m, 1H), 3.59(m, 1H), 3.39 (m, 1H), 2.98 (m, 1H), 2.69 (m, 1H), 2.31 (m, 1H), 2.15(m, 1H).

Example 1.1.7. (R)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-88) and(R)-2-((R)-7-fluoroisochroman-1-yl)azetidine (I-87)

(R)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-88) and(R)-2-((R)-7-fluoroisochroman-1-yl)azetidine (I-87) were prepared usinga procedure analogous to that described in Example 1.1.1, but using2-(4-fluorophenyl)ethanol in place of 2-phenylethanol and (R)-tert-butyl2-formylazetidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-88): MS (ESI) m/z: 208(M+H)⁻¹. ¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.20˜7.16 (q, J=6.4 Hz, 1H),6.96˜6.91 (m, 2H), 4.77 (d, J=4.8 Hz, 1H), 4.40˜4.34 (m, 1H), 4.28˜4.24(m, 1H), 3.80˜3.73 (m, 1H), 3.65˜3.59 (q, J=8.4 Hz, 1H), 3.48˜3.42 (m,1H), 3.04˜2.96 (m, 1H), 2.71˜2.67 (m, 1H), 2.35˜2.21 (m, 1H), 2.19˜2.12(m, 1H).

(R)-2-((R)-7-fluoroisochroman-1-yl)azetidine (I-87): MS (ESI) m/z: 208(M+H)⁺¹. ¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.18˜7.15 (q, J=5.6 Hz, 1H),6.95˜6.87 (m, 2H), 4.69 (d, J=5.6 Hz, 1H), 4.32˜4.21 (m, 2H), 3.80˜3.74(m, 1H), 3.61˜3.55 (q, J=8.4 Hz, 1H), 3.40˜3.32 (m, 1H), 3.06˜2.98 (m,1H), 2.72˜2.63 (m, 2H), 2.43˜2.35 (m, 1H).

Example 1.1.8. (R)-2-((S)-isochroman-1-yl)azetidine (I-81) and(R)-2-((R)-isochroman-1-yl)azetidine (I-82)

(R)-2-((S)-isochroman-1-yl)azetidine (I-81) and(R)-2-((R)-isochroman-1-yl)azetidine (I-82) were prepared using aprocedure analogous to that described in Example 1.1.1, but using(R)-tert-butyl 2-formylazetidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-isochroman-1-yl)azetidine (I-81): MS (ESI) m/z: 190 (M+H)⁺¹.¹H NMR 400 MHz, CDCl₃) δ 7.25˜7.09 (m, 4H), 4.79˜4.78 (d, J=5.6 Hz, 1H),4.35˜4.18 (m, 2H), 3.78 (td, J₁=10.9, J₂=3.2 Hz, 1H), 3.62 (q, J=8.1 Hz,1H), 3.44˜3.39 (m, 1H), 3.07˜3.0 (m, 1H), 2.69˜2.65 (m, 1H), 2.59 (s,1H), 2.43˜2.31 (m, 1H), 2.18˜2.14 (m, 1H).

(R)-2-((R)-isochroman-1-yl)azetidine (I-82): MS (ESI) m/z: 190 (M+H)⁺¹.¹H NMR (400 MHz, CDCl₃) δ 7.25˜7.06 (m, 4H), 4.75˜4.739 (d, J=6.3 Hz,1H), 4.26˜4.21 (m, 2H), 3.87˜3.78 (m, 1H), 3.63 (dd, J₁=15.5, J₂=8.0 Hz,1H), 3.50˜3.42 (m, 1H), 3.08˜3.01 (m, 1H), 2.74˜2.69 (m, 1H), 2.66-2.55(m, 1H), 2.42˜2.36 (m, 2H).

Example 1.1.9. (R)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-96) and(R)-2-((R)-5-fluoroisochroman-1-yl)azetidine (I-95)

(R)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-96) and(R)-2-((R)-5-fluoroisochroman-1-yl)azetidine (I-95) were prepared usinga procedure analogous to that described in Example 1.1.1, but using2-(2-fluorophenyl)ethanol in place of 2-phenylethanol and (R)-tert-butyl2-formylazetidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-96): MS (ESI) m/z: 208(M+H)⁺¹. ¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.30˜7.24 (m, 1H), 7.04 (t,J=8.8 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 5.16 (d, J=13.4 Hz, 2H),4.53-4.42 (m, 1H), 4.07-3.97 (m, 1H), 3.92˜3.84 (m, 2H), 2.99˜2.95 (m,1H), 2.88˜2.83 (m, 1H), 2.42-2.19 (m, 2H).

(R)-2-((R)-5-fluoroisochroman-1-yl)azetidine (I-95): MS (ESI) m/z: 208(M+H)⁺¹. ¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.33˜7.27 (m, 1H), 7.08˜7.03(m, 1H), 5.15 (s, 1H), 5.02 (s, 1H), 4.43˜4.38 (m, 1H), 4.09˜4.06 (m,1H), 3.91˜3.84 (m, 2H), 3.03˜2.96 (m, 1H), 2.83˜2.79 (m, 1H), 2.64˜2.62(m, 1H).

Example 1.1.10. (R)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-91) and(R)-2-((R)-6-fluoroisochroman-1-yl)azetidine (I-92)

(R)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-91) and(R)-2-((R)-6-fluoroisochroman-1-yl)azetidine (I-92) were prepared usinga procedure analogous to that described in Example 1.1.1, but using2-(3-fluorophenyl)ethanol in place of 2-phenylethanol and (R)-tert-butyl2-formylazetidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-91): MS (ESI) m/z: 208(M+H)⁺¹. ¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.25 (dd, J=8.5, 5.7 Hz,1H), 7.02 (dd, J=13.0, 5.7 Hz, 2H), 5.11 (td, J=8.6, 3.7 Hz, 1H), 4.99(s, 1H), 4.35 (ddd, J=11.3, 6.0, 1.7 Hz, 1H), 4.17-3.99 (m, 1H),3.97-3.75 (m, 2H), 3.22 (ddd, J=17.1, 11.4, 6.0 Hz, 1H), 3.08-2.88 (m,1H), 2.74 (d, J=16.7 Hz, 1H), 2.68-2.50 (m, 1H).

(R)-2-((R)-6-fluoroisochroman-1-yl)azetidine (I-92): MS (ESI) m/z: 208(M+H)⁺¹. ¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.15 (dd, J=8.3, 5.5 Hz,1H), 6.98 (dd, J=15.4, 6.3 Hz, 2H), 5.12 (p, J=3.2 Hz, 2H), 4.41 (dd,J=11.3, 5.9 Hz, 1H), 4.02 (td, J=9.8, 8.0 Hz, 1H), 3.96-3.78 (m, 2H),3.28-3.09 (m, 1H), 2.76 (d, J=16.6 Hz, 1H), 2.44-2.18 (m, 2H).

Example 1.1.11. (S)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine (I-30)and (S)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine (I-29)

(S)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine (I-30) and(S)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine (I-29) were preparedusing a procedure analogous to that described in Example 1.1.1, butusing 2-(4-chlorophenyl)ethanol in place of 2-phenylethanol.

(S)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine (I-30): MS (ESI) m/z: 238(M+H)⁺¹. ¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.32-7.33 (m, 1H), 7.13-7.21(m, 2H), 4.79 (s, 1H), 4.20-4.25 (m, 1H), 3.70-3.77 (m, 1H), 3.61-3.66(m, 1H), 2.98-3.08 (m, 2H), 2.64-2.77 (m, 2H), 1.95-2.01 (m, 2H),1.81-1.88 (m, 2H).

(S)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine (I-29): MS (ESI) m/z: 238(M+H)⁺¹. ¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.23 (s, 1H), 7.14-7.21 (m,2H), 4.93 (s, 1H), 4.20-4.24 (m, 1H), 3.67-3.74 (m, 1H), 3.59-3.64 (m,1H), 3.08-3.14 (m, 1H), 2.95-3.04 (m, 1H), 2.78-2.84 (m, 1H), 2.63-2.67(J=16.4 Hz, d, 1H), 1.70-1.78 (m, 2H), 1.45-1.51 (m, 2H).

Example 1.1.12. (S)-2-((S)-7-methylisochroman-1-yl)pyrrolidine (I-26)and (S)-2-((R)-7-methylisochroman-1-yl)pyrrolidine (I-25)

(S)-2-((S)-7-methylisochroman-1-yl)pyrrolidine (I-26) and(S)-2-((R)-7-methylisochroman-1-yl)pyrrolidine (I-25) were preparedusing a procedure analogous to that described in Example 1.1.1, butusing 2-(p-tolyl)ethanol in place of 2-phenylethanol.

(S)-2-((S)-7-methylisochroman-1-yl)pyrrolidine (I-26): MS (ESI) m/z: 218(M+H)⁺¹.

(S)-2-((R)-7-methylisochroman-1-yl)pyrrolidine (I-25): MS (ESI) m/z: 218(M+H)⁺¹.

Example 1.1.13. (R)-2-((S)-7-methylisochroman-1-yl)pyrrolidine (I-27)and (R)-2-((R)-7-methylisochroman-1-yl)pyrrolidine (I-28)

(R)-2-((S)-7-methylisochroman-1-yl)pyrrolidine (I-27) and(R)-2-((R)-7-methylisochroman-1-yl)pyrrolidine (I-28) were preparedusing a procedure analogous to that described in Example 1.1.1, butusing 2-(p-tolyl)ethanol in place of 2-phenylethanol and (R)-tert-butyl2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-7-methylisochroman-1-yl)pyrrolidine (I-27): MS (ESI) m/z: 218(M+H)⁺¹.

(R)-2-((R)-7-methylisochroman-1-yl)pyrrolidine (I-28): MS (ESI) m/z: 218(M+H)⁺¹.

Example 1.1.14. (R)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine (I-32)and (R)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine (I-31)

(R)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine (I-32) and(R)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine (I-31) were preparedusing a procedure analogous to that described in Example 1.1.1, butusing 2-(4-chlorophenyl)ethanol in place of 2-phenylethanol and(R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine (I-32): MS (ESI) m/z: 238(M+H)⁺¹.

(R)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine (I-31): MS (ESI) m/z: 238(M+H)⁺¹.

Example 1.1.15. (S)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine (I-33)and (S)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine (I-34)

(S)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine (I-33) and(S)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine (I-34) were preparedusing a procedure analogous to that described in Example 1.1.1, butusing 2-(3-chlorophenyl)ethanol in place of 2-phenylethanol.

(S)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine (I-33): (ESI) m/z:238[M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ 7.21-7.15 (m, 2H), 7.12 (s, 1H),4.74 (d, J=3.6 Hz, 1H), 4.24-4.19 (m, 1H), 3.77-3.71 (m, 1H), 3.63-3.58(m, 1H), 3.08-3.00 (m, 2H), 2.82-2.76 (m, 2H), 2.66 (m, 1H), 1.94-1.77(m, 4H).

(S)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine (I-34): (ESI) m/z:238[M+H]⁺. ¹H-NMR (400 MHz, MeOD): δ 7.28-7.21 (m, 3H), 5.19 (s, 1H),4.38-4.29 (m, 2H), 3.83-3.76 (td, J¹=2.8 Hz, J²=12.0 Hz, 1H), 3.38-3.32(m, 2H), 3.14-3.06 (m, 1H), 2.73-2.69 (m, 1H), 2.09-1.93 (m, 2H),1.80-1.74 (m, 2H).

Example 1.1.16. (R)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine (I-36)and ((R)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine (I-35)

(R)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine (I-36) and(R)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine (I-35) were preparedusing a procedure analogous to that described in Example 1.1.1, butusing 2-(3-chlorophenyl)ethanol in place of 2-phenylethanol and(R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine (I-36): MS (ESI+): m/z238 [M+H]; ¹H NMR (300 MHz, DMSO-d₆) 39.65 (s, 1H), 8.70 (s, 1H),7.40-7.20 (m, 3H), 5.12 (s, 1H), 4.40-4.10 (m, 2H), 3.71 (td, J=11.5,2.9 Hz, 1H), 3.27-3.06 (m, 2H), 3.06-2.92 (m, 1H), 2.69 (d, J=16.7 Hz,1H), 1.97-1.45 (m, 4H).

(R)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine (I-35): MS (ESI): m/z 238[M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆) 39.55 (s, 1H), 8.28 (s, 1H), 7.37-7.24(m, 3H), 4.94 (d, J=4.1 Hz, 1H), 4.21-4.06 (m, 2H), 3.73 (td, J=10.9,3.6 Hz, 1H), 3.15-3.00 (m, 3H), 2.70 (d, J=16.7 Hz, 1H), 2.09-1.79 (m,4H).

Example 1.1.17. (S)-2-((S)-isochroman-1-yl)piperidine (I-71) and(S)-2-((R)-isochroman-1-yl)piperidine (I-72)

(S)-2-((S)-isochroman-1-yl)piperidine (I-71) and(S)-2-((R)-isochroman-1-yl)piperidine (I-72) were prepared using aprocedure analogous to that described in Example 1.1.1, but using(S)-tert-butyl 2-formylpiperidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(S)-2-((S)-isochroman-1-yl)piperidine (I-71): MS (ESI): m/z 218 [M+H]⁺.¹HNMR (400 MHz, MeOD): δ 7.30-7.32 (m, 3H), 7.25 (m, 1H), 4.88 (s, 1H),4.28-4.30 (m, 1H), 3.71-3.79 (m, 2H), 3.23-3.26 (m, 1H), 3.07-3.13 (m,1H), 2.90-2.96 (m, 1H), 2.69-2.73 (d, J=16, 1H), 2.05-2.07 (m, 3H),1.99-2.01 (m, 1H), 1.69-1.91 (m, 2H).

(S)-2-((R)-isochroman-1-yl)piperidine (I-72): MS (ESI): m/z 218 [M+H]⁺.¹HNMR (400 MHz, MeOD): δ 7.18-7.29 (m, 4H), 5.10 (s, 1H), 4.28-4.32 (m,1H), 3.74-3.80 (m, 2H), 3.41-3.45 (m, 1H), 3.02-3.19 (m, 2H), 2.66-2.70(d, J=16, 1H), 1.81-2.03 (m, 2H), 2.05-2.07 (m, 3H), 1.99-2.01 (m, 1H).

Example 1.1.18. (S)-2-((S)-6-fluoroisochroman-1-yl)piperidine (I-73) and(S)-2-((R)-6-fluoroisochroman-1-yl)piperidine (I-74)

(S)-2-((S)-6-fluoroisochroman-1-yl)piperidine (I-73) and(S)-2-((R)-6-fluoroisochroman-1-yl)piperidine (I-74) were prepared usinga procedure analogous to that described in Example 1.1.1, but using2-(3-fluorophenyl)ethanol in place of 2-phenylethanol and (S)-tert-butyl2-formylpiperidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(S)-2-((S)-6-fluoroisochroman-1-yl)piperidine (I-73): MS (ESI): m/z 236[M+H]⁺, ¹HNMR (400 MHz, MeOD): δ 7.34-7.37 (m, 1H), 6.99-7.09 (m, 2H),4.87 (s, 1H), 4.27-4.32 (m, 1H), 3.71-3.80 (m, 2H), 3.24-3.28 (m, 1H),3.05-3.13 (m, 1H), 2.92-2.97 (m, 1H), 2.70-2.74 (d, J=16, 1H), 1.89-2.08(m, 4H), 1.66-1.72 (m, 2H).

(S)-2-((R)-6-fluoroisochroman-1-yl)piperidine (I-74): MS (ESI): m/z 236[M+H]⁺, ¹HNMR (400 MHz, MeOD): δ 7.21-7.24 (m, 1H), 6.98-7.05 (m, 2H),5.07 (s, 1H), 4.28-4.32 (m, 1H), 3.73-3.79 (m, 2H), 3.41-3.45 (m, 1H),3.02-3.18 (m, 2H), 2.67-2.71 (d, J=16, 1H), 1.82-1.91 (m, 2H), 1.49-1.72(m, 3H), 1.36-1.40 (m, 1H).

Example 1.1.19.(S)-2-((S)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-yl)pyrrolidine(I-53) and(S)-2-((R)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-yl)pyrrolidine(I-54)

(S)-2-((S)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-yl)pyrrolidine(I-53) and(S)-2-((R)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-yl)pyrrolidine(I-54) were prepared using a procedure analogous to that described inExample 1.1.1, but using 2-(benzo[d][1,3]dioxol-5-yl)ethanol in place of2-phenylethanol.

(S)-2-((S)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-yl)pyrrolidine(I-53): MS (ESI): m/z 248 (M+H)⁺. ¹H NMR (HCl salt, 400 MHz, MeOD) δ6.81 (t, J=40.4 Hz, 2H), 5.95 (d, J=0.5 Hz, 2H), 4.94 (s, 1H), 4.25(ddd, J=11.2, 5.8, 1.7 Hz, 1H), 4.22-4.03 (m, 1H), 3.77 (td, J=11.3, 3.2Hz, 1H), 3.31-3.17 (m, 2H), 3.16-3.02 (m, 1H), 2.59 (d, J=16.3 Hz, 1H),2.33-2.19 (m, 2H), 2.20-1.98 (m, 2H).

(S)-2-((R)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-yl)pyrrolidine(I-54): MS (ESI): m/z 248 (M+H)⁺. ¹H NMR (HCl salt, 400 MHz, MeOD) δ6.70 (d, J=9.1 Hz, 2H), 5.94 (d, J=1.7 Hz, 2H), 5.11 (s, 1H), 4.36-4.12(m, 2H), 3.84-3.61 (m, 1H), 3.35 (d, J=8.3 Hz, 2H), 3.10-2.90 (m, 1H),2.59 (d, J=16.2 Hz, 1H), 2.15-1.86 (m, 2H), 1.78 (td, J=8.4, 3.8 Hz,2H).

Example 1.1.20. (S)-2-((R)-6-bromoisochroman-1-yl)pyrrolidine (I-145)

(S)-2-((R)-6-bromoisochroman-1-yl)pyrrolidine (I-145) were preparedusing a procedure analogous to that described in Example 1.1.1, butusing 2-(3-bromophenyl)ethanol in place of 2-phenylethanol.

(S)-2-((R)-6-bromoisochroman-1-yl)pyrrolidine (I-145): MS (ESI): m/z 282(M+H)⁺. ¹H NMR (400 MHz, CDCl3) δ 7.29-7.03 (m, 2H), 7.04 (d, J=8.4 Hz,1H), 4.86 (d, J=2.4 Hz, 1H), 4.18-4.13 (m, 1H), 3.71-3.64 (m, 1H),3.53-3.48 (m, 1H), 3.12-2.96 (m, 2H), 2.83-2.76 (m, 1H), 2.58 (d, J=16.4Hz, 1H), 2.17 (br, 1H), 1.70-1.63 (m, 2H), 1.45-1.39 (m, 2H).

Example 1.2. Procedure B. Certain Provided Compounds were Made Followinga Procedure Exemplified by Example 1.2.1 Example 1.2.1.(S)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (I-10) and(S)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-9)

(a). (2-bromo-5-fluorophenethoxy)(tert-butyl)dimethylsilane

To a solution of 2-(2-bromo-5-fluorophenyl)ethanol (23.2 g, 105.91 mmol)in DCM (300 mL) was added 1H-imidazole (14.4 g, 211.8 mmol) andtert-butylchlorodimethylsilane (20.8 g, 137.7 mmol). After the mixturewas stirred at room temperature overnight, it was quenched with H₂O (300mL) at 0° C. The resulting mixture was extracted with DCM (2×100 mL).The combined organic layers were washed with brine (400 mL), dried oversodium sulfate, filtered, and concentrated. The crude product waspurified by silica gel chromatography (eluted with petroleum ether:ethylacetate=40:1) to give (2-bromo-5-fluorophenethoxy)(tert-butyl)dimethylsilane. MS (ESI): m/z 333 [M+H]⁺, 32.3 g colorlessoil.

(b). (2S)-tert-butyl2-((2-(2-(tert-butyldimethylsilyloxy)ethyl)-4-fluorophenyl)(hydroxy)-methyl)pyrrolidine-1-carboxylate

To a mixture of (2-bromo-5-fluorophenethoxy)(tert-butyl)dimethylsilane(5.0 g, 15.0 mmol) in toluene (60 mL) was added n-butyllithium (2.4 M,12.5 mL, 30.0 mmol) at −78° C. After stirred at −78° C. for 1 h,(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (4.48 g, 22.5 mmol) intoluene (10 mL) was added at −78° C. The mixture was stirred at −78° C.for 2 h. Upon completion, sat. NH₄Cl solution (100 mL) and EtOAc (50 mL)was added. The organic layer was separated, washed with brine, dried,filtered, and concentrated. The crude product was purified by silica gel(eluted from PE:EtOAc=100:1 to PE:EtOAc=20:1) to yield the desiredcompound: 2.5 g colorless oil. (ESI) m/z: 454 (M+H)⁺.

(c). (2S)-tert-butyl2-((4-fluoro-2-(2-hydroxyethyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate

To a solution of (2S)-tert-butyl2-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate(2.5 g, 5.07 mmol) in THF (50 mL) was added TBAF (2.64 g, 10.14 mmol) atroom temperature. The mixture was stirred at room temperature for 3 h.The mixture was evaporated in vacuo. The residue was dissolved in EtOAc(100 mL) and washed with water (80 mL×2). The organic layer was dried,filtered and concentrated in vacuo to give the crude product. The crudewas purified by reverse flash column (mobile phase: MeCN and 0.1%aqueous ammonia) to afford the desired product: 1.2 g yellow oil.

(d). (2S)-tert-butyl 2-((4-fluoro-2-(2-(methylsulfonyloxy)ethyl)phenyl)(hydroxy)methyl)-pyrrolidine-1-carboxylate

To a solution of (2S)-tert-butyl2-((4-fluoro-2-(2-hydroxyethyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (1.0 g, 2.95 mmol) in ethyl acetate (50mL) was added methanesulfonyl chloride (372 mg, 3.2 mmol) andtriethylamine (894 mg, 8.85 mmol) at 0° C. The mixture was stirred atroom temperature for 2 h. Upon completion, aq NaHCO₃ (10 mL) was addedto the mixture. The organic layer was separated, washed with water(3×150 mL), dried over Na₂SO₄, filtered and concentrated to give theproduct: 1.2 g light yellow oil.

(e). (2S)-tert-butyl2-(6-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate

To a solution of (2S)-tert-butyl2-((4-fluoro-2-(2-((methylsulfonyl)oxy)ethyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (1.2 g, 2.44 mmol) intetrahydrofuran (80 mL) was added potassium t-butoxide (0.55 g, 4.9mmol) at 0° C. The mixture was stirred at room temperature for 2 h. Uponcompletion, the mixture was concentrated, diluted with EtOAc (60 mL),washed with water (3×40 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated to give the crude product as a yellow oil (600mg).

(f). (2S)-2-(6-fluoroisochroman-1-yl)pyrrolidine

A solution of (2S)-tert-butyl2-(6-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate (600 mg, 1.87 mmol)in 4 N HCl/dioxane (10 mL) was stirred at room temperature for 3 h. Themixture was evaporated in vacuo to give the crude product: 390 mgoff-white solid. (ESI) m/z: 222[M+H]⁺.

(g). (S)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (I-10) and(S)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-9)

(2S)-2-(6-fluoroisochroman-1-yl)pyrrolidine from previous step (2batches) (780 mg, 3.52 mmol) was separated by preparative HPLC to givethe two diastereoisomers, which were separately further purified bychiral column chromatography: Column AY-H (250*4.6 mm 5 μm) and MobliePhase: n-Hexane (0.1% DEA):EtOH (0.1% DEA)=80:20 to give(S)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (160 mg yellow oil, (ESI)m/z: 222[M+H]⁺) and (S)-2-((R)-6-fluoroisochroman-1-yl) pyrrolidine (180mg yellow oil, (ESI) m/z: 222[M+H]⁺).

¹HNMR of (S)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (I-10) (400 MHz,CDCl₃): δ 7.23-7.19 (m, 1H), 6.90-6.85 (m, 1H), 6.81-6.79 (m, 1H), 4.71(d, J=2.4 Hz, 1H), 4.21-4.16 (m, 1H), 3.76-3.69 (m, 1H), 3.57-3.52 (m,1H), 3.06-2.98 (m, 2H), 2.79-2.73 (m, 1H), 2.65 (d, J=16.4 Hz, 1H), 2.45(brs, 1H), 1.90-1.73 (m, 4H).

¹HNMR of (S)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-9) (400 MHz,CDCl₃): δ 7.17-7.14 (m, 1H), 6.92-6.82 (m, 2H), 4.93 (s, 1H), 4.22-4.17(m, 1H), 3.76-3.69 (m, 1H), 3.58-3.53 (m, 1H), 3.17-3.00 (m, 2H),2.87-2.80 (m, 1H), 2.64-2.60 (m, 1H), 2.20 (brs, 1H), 1.74-1.66 (m, 2H),1.49-1.43 (m, 2H).

Example 1.2.2. (2S)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-6) and(2S)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine (I-5)

(2S)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-6) and(2S)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine (I-5) were preparedusing using a procedure analogous to that described in Example 1.2.1,but using 2-(2-bromo-4-fluorophenyl) ethanol in place of2-(2-bromo-5-fluorophenyl)ethanol.

(2S)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-6): MS (ESI): m/z 222[M+H]⁺, ¹H NMR (400 MHz, CDCl3): δ 7.06-7.09 (m, 1H), 6.85-6.92 (m, 2H),4.92 (s, 1H), 4.18-4.22 (m, 1H), 3.67-3.74 (m, 1H), 3.51-3.56 (m, 1H),3.10-3.16 (m, 1H), 2.94-3.03 (m, 1H), 2.81-2.87 (m, 1H), 2.51-2.62 (m,2H), 1.67-1.74 (m, 2H), 1.44-1.50 (m, 2H).

(2S)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine (I-5): MS (ESI): m/z 222[M+H]⁺, ¹H NMR (400 MHz, CDCl3): δ 7.06-7.09 (m, 1H), 6.93-6.86 (m, 2H),4.93 (s, 1H), 4.23-4.18 (m, 1H), 3.74-3.68 (m, 1H), 3.56-3.51 (m, 1H),3.17-3.11 (m, 1H), 3.03-2.94 (m, 1H), 2.88-2.81 (m, 1H), 2.61 (d, 1H),2.52 (s, br. 1H), 1.74-1.67 (m, 2H), 1.51-1.45 (m, 2H).

Example 1.2.3. ((S)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine (I-14)and (S)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine (I-13)

((S)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine (I-14) and(S)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine (I-13) were preparedusing a procedure analogous to that described in Example 1.2.1, butusing 2-(2-bromo-6-fluorophenyl)ethanol in place of2-(2-bromo-5-fluorophenyl)ethanol.

((S)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine (I-14): MS (ESI) m/z222.1 (M+H)⁺¹. ¹H NMR (400 MHz, MeOD): δ 7.28˜7.22 (m, 1H), 7.12 (d,J=8.0 Hz, 1H), 6.99˜6.95 (q, J=4.4 Hz, 1H), 4.82 (d, J=2.4 Hz, 1H),4.30˜4.25 (m, 1H), 3.79˜3.72 (m, 2H), 3.07˜3.01 (m, 1H), 2.95˜2.75 (m,3H), 2.06˜2.00 (m, 2H) 1.96˜1.79 (m, 2H).

(S)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine (I-13): MS (ESI) m/z222.1 (M+H)⁺¹. ¹H NMR (400 MHz, MeOD): δ 7.25˜7.19 (m, 1H), 7.03 (d,J=8.0 Hz, 1H), 6.97˜6.92 (q, J=4.4 Hz, 1H), 4.96 (d, J=0.8 Hz, 1H),4.28˜4.23 (m, 1H), 3.73˜3.63 (m, 2H), 3.14˜3.09 (m, 1H), 2.88˜2.73 (m,3H), 1.76˜1.69 (m, 2H) 1.51˜1.41 (m, 2H).

Example 1.2.4. (R)-2-((S)-isochroman-1-yl)pyrrolidine (I-20) and(R)-2-((R)-isochroman-1-yl)pyrrolidine (I-19)

(R)-2-((S)-isochroman-1-yl)pyrrolidine (I-20) and(R)-2-((R)-isochroman-1-yl)pyrrolidine (I-19) were prepared using aprocedure analogous to that described in Example 1.2.1, but using2-(2-bromophenyl)ethanol in place of 2-(2-bromo-5-fluorophenyl)ethanoland (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-isochroman-1-yl)pyrrolidine (I-20): m/z=204[M+1]+. ¹H NMR(400 MHz, CDCl3) δ 7.24-7.05 (m, 4H), 4.98 (d, J=1.7 Hz, 1H), 4.21˜4.16(m, 1H), 3.76˜3.69 (td, J=11.3, 3.0 Hz, 1H), 3.60˜3.57 (td, J=7.9, 3.5Hz, 1H), 3.14˜3.04 (m, 2H), 2.85˜2.81 (m, 1H), 2.73 (s, 1H), 2.62˜2.58(d, J=16.1 Hz, 1H), 1.75-1.61 (m, 2H), 1.53-1.38 (m, 2H).

(R)-2-((R)-isochroman-1-yl)pyrrolidine (I-19): m/z=204[M+1]+. ¹H NMR(HCl salt, 400 MHz, MeOD) δ 7.36-7.18 (m, 4H), 5.04 (d, J=2.4 Hz, 1H),4.34-4.22 (m, 2H), 3.83 (td, J=11.3, 3.3 Hz, 1H), 3.32-3.14 (m, 3H),2.71 (d, J=16.4 Hz, 1H), 2.34-2.03 (m, 4H).

Example 1.2.5. (R)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-8) and(R)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine (I-7)

(R)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-8) and(R)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine (I-7) were prepared usinga procedure analogous to that described in Example 1.2.1, but using2-(2-bromo-4-fluorophenyl) ethanol in place of2-(2-bromo-5-fluorophenyl)ethanol and (R)-tert-butyl2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-8): m/z=222 [M+1]+.¹HNMR (400 MHz, CDCl₃): δ 7.07-7.11 (m, 1H), 6.87-6.93 (m, 2H), 4.93 (s,1H), 4.19-4.23 (m, 1H), 3.69-3.75 (m, 1H), 3.51-3.55 (m, 1H), 3.11-3.17(m, 1H), 2.99-3.00 (m, 1H), 2.81-2.88 (m, 1H), 2.60-2.63 (J=15.6 Hz, d,1H), 1.68-1.73 (m, 2H), 1.45-1.49 (m, 2H).

(R)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine (I-7): m/z=222[M+1⁺.¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.14-7.18 (m, 1H), 7.03-7.06 (m, 1H),6.91-6.96 (m, 1H), 4.77 (s, 1H), 4.20-4.24 (m, 1H), 3.70-3.76 (m, 1H),3.58-3.62 (m, 1H), 2.99-3.03 (m, 2H), 2.63-2.75 (m, 2H), 1.94-2.00 (m,2H), 1.80-1.87 (m, 2H).

Example 1.2.6. (R)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (I-11) and(R)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-12)

(R)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (I-11) and(R)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-12) were preparedusing a procedure analogous to that described in Example 1.2.1, butusing (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (I-11): ESI: m/z=222(M+H⁺). ¹HNMR (400 MHz, CDCl₃): δ 7.21 (dd, J¹=5.6 Hz, J²=8.4 Hz, 1H),6.88 (td, J¹=2.8 Hz, J²=8.4 Hz, 1H), 6.79 (dd, J¹=2.4 Hz, J²=9.2 Hz,1H), 4.69 (d, J=3.2 Hz, 1H), 4.19 (m, 1H), 3.73 (m, 1H), 3.56 (m, 1H),3.03 (m, 2H), 2.77 (m, 1H), 2.63 (m, 1H), 2.48 (brs, 1H), 1.87-1.68 (m,4H).

(R)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-12): ESI: m/z=222(M+H⁺). ¹HNMR of freebase (400 MHz, CDCl₃): δ 7.11 (dd, J¹=5.6 Hz,J²=8.8 Hz, 1H), 6.85 (td, J¹=2.8 Hz, 12=8.8 Hz, 1H), 6.77 (dd, J¹=2.4Hz, 12=9.2 Hz, 1H), 4.87 (s, 1H), 4.15 (m, 1H), 3.69 (td, J¹=2.8 Hz,12=11.2 Hz, 1H), 3.53 (m, 1H), 3.10-2.95 (m, 2H), 2.81-2.74 (m, 1H),2.58-2.53 (m, 2H), 1.67-1.60 (m, 2H), 1.45-1.38 (m, 2H).

Example 1.2.7. (S)-2-((S)-4,4-difluoroisochroman-1-yl)pyrrolidine(I-139) and (S)-2-((R)-4,4-difluoroisochroman-1-yl)pyrrolidine (I-140)

(S)-2-((S)-4,4-difluoroisochroman-1-yl)pyrrolidine (I-139) and(S)-2-((R)-4,4-difluoro-isochroman-1-yl)pyrrolidine (I-140) wereprepared using a procedure analogous to that described in Example 1.2.1,but using 2-(2-bromophenyl)-2,2-difluoroethanol in place of2-(2-bromo-5-fluorophenyl)ethanol.

(S)-2-((S)-4,4-difluoroisochroman-1-yl)pyrrolidine (I-139): MS (ESI):m/z=240[M+H]⁺; 1H NMR (HCl salt, 400 MHz, MeOD) 7.80˜7.78 (m, 1H),7.65˜7.54 (m, 2H), 7.50˜7.48 (m, 1H), 5.16 (brs, 1H), 4.47˜4.39 (m, 1H),4.38˜4.34 (m, 1H), 4.17˜4.07 (m, 1H), 3.27˜3.22 (m, 2H), 2.39˜2.23 (m,2H), 2.18˜2.08 (m, 2H).

(S)-2-((R)-4,4-difluoro-isochroman-1-yl)pyrrolidine (I-140): MS (ESI):m/z=240[M+H]⁺; 1H NMR (HCl salt, 400 MHz, MeOD) 7.76˜7.75 (m, 1H),7.60˜7.50 (m, 2H), 7.41˜7.39 (m, 1H), 5.34 (brs, 1H), 4.54˜4.50 (m, 1H),4.45˜4.39 (m, 1H), 4.10˜4.00 (m, 1H), 3.41˜3.30 (m, 2H), 2.07˜1.95 (m,2H), 1.82˜1.60 (m, 2H).

Example 1.3. Procedure C. Certain Provided Compounds were Made Followinga Procedure Exemplified by Example 1.3.1 Example 1.3.1.(S)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-2) and(S)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine (I-1)

(a). (2S)-tert-butyl 2-(5-bromo-8-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate

(2S)-tert-butyl 2-(5-bromo-8-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate was prepared using a procedure analogous tothat described in Example 1.1.1 (step a and step b), but using2-(2-bromo-5-fluorophenyl)ethanol in place of 2-phenylethanol.

(b). (2S)-tert-butyl 2-(8-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate

A mixture of(2S)-tert-butyl-2-(5-bromo-8-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate(2.0 g, 5.0 mmol) and 10% dry Pd/C (320 mg) in methanol (40 mL) wasstirred at room temperature under hydrogen for 2 h. The reaction mixturewas filtered and the filtrate was concentrated in vacuo to give thecrude, which was purified by preparative HPLC to give the desiredproduct, 1.3 g, as a light yellow oil.

(c). (S)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-2) and(S)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine (I-1)

(S)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-2) and(S)-2-((R)-8-fluoroisochroman-1-yl)-pyrrolidine (I-1) were preparedusing a procedure similar to that described in Example 1.1.1 (step c andstep d).

(S)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-2): (ESI) m/z:222[M+H]⁺. ¹HNMR (400 MHz, CDCl₃): δ 7.19-7.14 (q, J=5.6 Hz, 1H),6.93-6.87 (m, 2H), 5.42 (brs, 1H), 5.03 (d, J=4.0 Hz, 1H), 4.27-4.20 (m,1H), 3.87-3.82 (m, 1H), 3.71-3.65 (td, J¹=3.6 Hz, J²=10.4 Hz, 1H),3.15-3.01 (m, 2H), 2.89-2.83 (m, 1H), 2.70-2.64 (m, 1H), 2.05-1.75 (m,4H).

(S)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine (I-1): (ESI) m/z:222[M+H]⁺. ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.35-7.30 (q, J=7.6 Hz,1H), 7.10 (d, J=7.6 Hz, 1H), 7.04 (t, J=9.6 Hz, 1H), 5.37 (s, 1H),4.45-4.41 (td, J¹=2.4 Hz, J²=8.0 Hz, 1H), 4.33 (q, J=5.6 Hz, 1H),3.78-3.72 (td, J¹=2.0 Hz, J²=11.6 Hz, 1H), 3.37 (m, 2H), 3.14 (m, 1H),2.77 (d, J=16.4 Hz, 1H), 2.11-1.93 (m, 2H), 1.83-1.71 (m, 2H).

Example 1.3.2. (R)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-3) and(R)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine (I-4)

(R)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-3) and(R)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine (I-4) were prepared usinga procedure analogous to that described in Example 1.3.1, but using(R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-3): ESI: m/z=222(M+H⁺). ¹HNMR (400 MHz, CDCl₃): δ 7.18 (m, 1H), 6.93 (m, 2H), 5.19 (s,1H), 4.20 (m, 1H), 3.84 (m, 1H), 3.67 (td, J¹=2.8 Hz, J²=11.6 Hz, 1H),3.14-2.97 (m, 2H), 2.87 (m, 1H), 2.64 (s, 1H), 2.60 (brs, 1H), 1.74-1.65(m, 2H), 1.49-1.37 (m, 2H).

(R)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine (I-4): ESI: m/z=222(M+H⁺). ¹HNMR (400 MHz, CDCl₃): δ 7.18 (m, 1H), 6.93 (m, 2H), 4.99 (d,J=3.2 Hz, 1H), 4.26 (m, 1H), 3.72 (m, 2H), 3.08 (m, 2H), 2.80 (m, 2H),2.16 (brs, 1H), 1.93-1.72 (m, 4H).

Example 1.3.3. (S)-2-((S)-8-fluoroisochroman-1-yl)azetidine (I-84) and(S)-2-((R)-8-fluoroisochroman-1-yl)azetidine (I-83)

(S)-2-((S)-8-fluoroisochroman-1-yl)azetidine (I-84) and(S)-2-((R)-8-fluoroisochroman-1-yl)azetidine (I-83) were prepared usinga procedure analogous to that described in Example 1.3.1, but using(S)-tert-butyl 2-formylazetidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(S)-2-((S)-8-fluoroisochroman-1-yl)azetidine (I-84): MS (ESI): m/z 208[M+H]⁺, ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.24-7.18 (m, 1H), 6.99 (d,J=7.6, 1H), 6.93 (t, 1H), 5.08 (s, 2H), 4.23-4.18 (m, 1H), 3.99-3.92 (d,J=9.6 Hz, 1H), 3.74-3.67 (m, 2H), 3.14-3.05 (m, 1H), 2.89-2.84 (m, 1H),2.66 (d, J=11.6, 1H), 2.43 (m, 1H).

(S)-2-((R)-8-fluoroisochroman-1-yl)azetidine (I-83): MS (ESI): m/z 208[M+H]⁺, ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.35-7.29 (m, 1H), 7.09 (d,J=7.6, 1H), 6.98 (t, 1H), 5.29 (s, 1H), 5.19 (t, 1H), 4.44-4.39 (m, 1H),4.04 (d, J=9.6 Hz, 1H), 3.93-3.78 (m, 2H), 3.18 (m, 1H), 2.82 (d, J=16,1 H), 2.38 (m, 2H).

Example 1.3.4. (S)-2-((S)-8-methylisochroman-1-yl)pyrrolidine (I-21) and(S)-2-((R)-8-methylisochroman-1-yl)pyrrolidine (I-22)

(S)-2-((S)-8-methylisochroman-1-yl)pyrrolidine (I-21) and(S)-2-((R)-8-methylisochroman-1-yl)pyrrolidine (I-22) were preparedusing a procedure analogous to that described in Example 1.3.1, butusing 2-(2-bromo-5-methylphenyl)ethanol in place of2-(2-bromo-5-fluorophenyl)ethanol.

(S)-2-((S)-8-methylisochroman-1-yl)pyrrolidine (I-21): ESI: m/z=218(M+H⁺). ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.14-7.22 (m, 2H), 7.08-7.09(J=7.2 Hz, d, 1H), 5.31 (s, 1H), 4.24-4.29 (m, 1H), 4.01-4.05 (m, 1H),3.60-3.66 (m, 1H), 3.36-3.38 (m, 1H), 3.20-3.24 (m, 2H), 2.66-2.70 (J=16Hz, d, 1H), 2.38 (s, 3H), 2.03-2.24 (m, 4H).

(S)-2-((R)-8-methylisochroman-1-yl)pyrrolidine (I-22): ESI: m/z=218(M+H⁺). ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.16-7.19 (J=14.8 Hz, t, 1H),7.05-7.11 (m, 2H), 5.44 (s, 1H), 4.21-4.27 (m, 2H), 3.60-2.67 (m, 1H),3.35-3.38 (m, 2H), 3.04-3.13 (m, 1H), 2.65-2.69 (J=16 Hz, d, 1H), 2.35(s, 3H), 1.90-2.06 (m, 2H), 1.76-1.83 (m, 1H), 1.56-1.59 (m, 1H).

Example 1.3.5. (R)-2-((S)-8-methylisochroman-1-yl)pyrrolidine (I-24) and(R)-2-((R)-8-methylisochroman-1-yl)pyrrolidine (I-23)

(R)-2-((S)-8-methylisochroman-1-yl)pyrrolidine (I-24) and(R)-2-((R)-8-methylisochroman-1-yl)pyrrolidine (I-23) were preparedusing a procedure analogous to that described in Example 1.3.1, butusing 2-(2-bromo-5-methylphenyl)ethanol in place of2-(2-bromo-5-fluorophenyl)ethanol and (R)-tert-butyl2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-8-methylisochroman-1-yl)pyrrolidine (I-24): ESI: m/z=218(M+H⁺). ¹H NMR (HCl salt, 400 MHz, MeOD): δ 7.05-7.19 (m, 3H), 5.44 (s,1H), 4.21-4.27 (m, 2H), 3.60-3.66 (m, 1H), 3.35-3.39 (m, 2H), 3.04-3.13(m, 1H), 2.65-2.69 (J=16.4 Hz, d, 1H), 2.35 (s, 3H), 1.90-2.06 (m, 2H),1.76-1.83 (m, 1H), 1.53-1.59 (m, 1H).

(R)-2-((R)-8-methylisochroman-1-yl)pyrrolidine (I-23): ESI: m/z=218(M+H⁺). ¹H NMR (HCl salt, 400 MHz, MeOD): δ 7.19-7.23 (J=14.8 Hz, t,1H), 7.14-7.16 (J=7.2 Hz, d, 1H), 7.08-7.09 (J=7.6 Hz, d, 1H), 5.31 (s,1H), 4.24-4.28 (m, 1H), 4.00-4.04 (m, 1H), 3.60-3.66 (m, 1H), 3.35-3.39(m, 1H), 3.17-3.26 (m, 2H), 2.66-2.70 (J=16 Hz, d, 1H), 2.36 (s, 3H),2.03-2.25 (m, 4H).

Example 1.3.6.((S)-2-((S)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)pyrrolidine(I-51) and(S)-2-((R)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)pyrrolidine(I-52)

(S)-2-((S)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)pyrrolidine(I-51) and(S)-2-((R)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)pyrrolidine(I-52) were prepared using a procedure analogous to that described inExample 1.3.1, but using 2-(6-bromobenzo[d][1,3]dioxol-5-yl)ethanol inplace of 2-(2-bromo-5-fluorophenyl)ethanol.

(S)-2-((S)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)pyrrolidine(I-51): ESI: M/Z=248[M+H]. 1H NMR (400 MHz, CDCl3) δ 6.68 (d, J=7.9 Hz,1H), 6.60 (d, J=7.9 Hz, 1H), 5.99 (d, J=1.5 Hz, 1H), 5.88 (d, J=1.5 Hz,1H), 4.86 (d, J=2.2 Hz, 1H), 4.21˜4.17 (m, 2.7 Hz, 1H), 3.85 (td,J₁=7.6, J₂=2.9 Hz, 1H), 3.68 (td, J₁=10.9, J₂=3.1 Hz, 1H), 3.08˜3.02 (m,1H), 3.00-2.89 (m, 1H), 2.79˜2.74 (m, 1H), 2.61˜2.56 (m, 1H), 2.17 (s,1H), 1.91˜1.75 (m, 4H).

(S)-2-((R)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)pyrrolidine(I-52): ESI: M/Z=248[M+H]⁺. H NMR (400 MHz, MeOD) δ 6.70 (d, J=8.0 Hz,1H), 6.63 (d, J=8.0 Hz, 1H), 5.94 (d, J=1.1 Hz, 1H), 5.86 (d, J=1.1 Hz,1H), 5.03 (s, 1H), 4.18˜4.14 (m, 1H), 3.96 (td, J₁=7.9, J₂=3.0 Hz, 1H),3.64 (td, J₁=11.5, J₂=2.7 Hz, 1H), 3.17-3.05 (m, 1H), 3.00-2.85 (m, 1H),2.81˜2.75 (m, 1H), 2.59˜2.55 (m, 1H), 1.75˜1.70 (m, 2H), 1.56˜1.48 (m,2H).

Example 1.3.7. (S)-2-((R)-8-methoxyisochroman-1-yl)pyrrolidine (I-47)and (S)-2-((S)-8-methoxyisochroma n-1-yl)pyrrolidine (I-48)

(S)-2-((R)-8-methoxyisochroman-1-yl)pyrrolidine (I-47) and(S)-2-((S)-8-methoxyisochroman-1-yl)pyrrolidine (I-48) were preparedusing a procedure analogous to that described in Example 1.3.1, butusing 2-(2-bromo-5-methoxyphenyl)ethanol in place of2-(2-bromo-5-fluorophenyl)ethanol.

(S)-2-((R)-8-methoxyisochroman-1-yl)pyrrolidine (I-47): MS (ESI): m/z234.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl3): δ 10.42 (s, 1H), 8.23 (s, 1H),7.19 (t, J=8.0 Hz, 1H), 6.76˜6.70 (q, J=7.6 Hz, 2H), 5.41 (s, 1H), 4.81(s, 1H), 4.26˜4.22 (q, J=5.2 Hz, 1H), 3.98˜3.82 (m, 1H), 3.70 (s, 3H),3.50˜3.44 (m, 2H), 3.05˜2.96 (m, 1H), 2.58 (d, J=16.0 Hz, 1H), 2.07˜1.88(m, 2H), 1.75˜1.61 (m, 1H).

(S)-2-((S)-8-methoxyisochroman-1-yl)pyrrolidine (I-48): MS (ESI): m/z234.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.46 (s, 1H), 7.87 (s, 1H),7.15 (t, J=8.0 Hz, 1H), 6.74˜6.71 (m, 2H), 5.02 (s, 1H), 4.46˜4.41 (m,1H), 4.23˜4.18 (m, 1H), 3.87 (s, 3H), 3.75˜3.67 (m, 1H), 3.61˜3.55 (m,1H), 3.11˜3.042 (m, 1H), 2.78˜2.72 (m, 1H), 2.51 (d, J=16.0 Hz, 1H),2.24˜2.16 (m, 1H), 2.04˜1.86 (m, 2H), 1.84˜1.78 (m, 1H).

Example 1.3.8. (R)-2-((R)-8-methoxyisochroman-1-yl)pyrrolidine (I-49)and (R)-2-((S)-8-methoxyisochroma n-1-yl)pyrrolidine (I-50)

(R)-2-((R)-8-methoxyisochroman-1-yl)pyrrolidine (I-49) and(R)-2-((S)-8-methoxyisochroman-1-yl)pyrrolidine (I-50) were preparedusing a procedure analogous to that described in Example 1.3.1, butusing 2-(2-bromo-5-methoxyphenyl)ethanol in place of2-(2-bromo-5-fluorophenyl)ethanol and (R)-tert-butyl2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(R)-2-((R)-8-methoxyisochroman-1-yl)pyrrolidine (I-49): MS (ESI): m/z234.1 (M+H)⁺. ¹H NMR (HCl salt, 400 MHz, MeOD): δ 7.19 (t, J=7.6 Hz,1H), 6.84 (d, J=8.0 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 5.04 (s, 1H),4.19˜4.14 (m, 1H), 3.86˜3.82 (m, 4H), 3.63˜3.56 (m, 1H), 3.09˜2.98 (m,2H), 2.74˜2.60 (m, 2H), 1.99˜1.81 (m, 4H).

(R)-2-((S)-8-methoxyisochroman-1-yl)pyrrolidine (I-50): MS (ESI): m/z234.1 (M+H)⁺. ¹H NMR (400 MHz, MeOD): δ 7.18 (t, J=7.6 Hz, 1H), 6.83 (d,J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 5.18 (s, 1H), 4.16˜4.12 (m, 1H),4.03˜4.01 (m, 1H), 3.99 (s, 3H), 3.82˜3.54 (m, 1H), 3.16˜3.10 (m, 1H),3.02˜2.93 (m, 1H), 2.60 (d, J=16.0 Hz, 1H), 1.78˜1.70 (m, 2H), 1.69˜1.53(m, 1H), 1.52˜1.48 (m, 1H).

Example 1.3.9.(S)-2-((S)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)azetidine(I-143) and(S)-2-((R)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)azetidine(I-144)

(S)-2-((S)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)azetidine(I-143) and(S)-2-((R)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)azetidine(I-144) were prepared using a procedure analogous to that described inExample 1.3.1, but using 2-(6-bromobenzo[d][1,3]dioxol-5-yl)ethanol inplace of 2-(2-bromo-5-fluorophenyl)ethanol and (S)-tert-butyl2-formylazetidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(S)-2-((S)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)azetidine(I-143): MS (ESI): m/z 234.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) 6.69˜6.59(m, 2H), 5.95 (s, 1H), 5.88 (s, 1H), 4.75˜4.74 (m, 1H), 4.61˜4.56 (m,1H), 4.29˜4.24 (m, 1H), 3.76˜3.72 (m, 1H), 3.58˜3.54 (m, 1H), 3.46˜3.41(m, 1H), 3.01˜2.93 (m, 1H), 2.70˜2.62 (m, 2H), 2.32˜2.02 (m, 1H).

(S)-2-((R)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)azetidine(I-144): MS (ESI): m/z 234.1 (M+H)⁺. ¹H NMR (400 MHz, MeOD) 6.78˜6.71(m, 2H), 5.98 (s, 1H), 5.93 (s, 1H), 5.28˜5.23 (m, 1H), 5.14˜5.13 (m,1H), 4.39˜4.36 (m, 1H), 4.02˜3.98 (m, 1H), 3.92˜3.80 (m, 2H), 3.08˜3.01(m, 1H), 2.71˜2.66 (m, 1H), 2.18˜2.08 (m, 2H).

Example 1.4. Procedure D. Certain Provided Compounds were Made Followinga Procedure Exemplified by Example 1.4.1 Example 1.4.1.(S)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-106) and(S)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-107)

(a). (3-(2-bromo-4-fluorophenyl)propoxy) (tert-butyl)dimethylsilane

To a solution of 3-(2-bromo-4-fluorophenyl)propanol (14.2 g, 60.9 mmol)in DCM (150 mL) was added imidazole (8.29 g, 121.8 mmol) and TBDMSCl(11.9 g, 79.2 mmol). The mixture was stirred at room temperature for 2 hand water (300 mL) was added. The mixture was extracted with DCM (3×150mL) and the organic layers were combined, washed, dried, filtered, andconcentrated in vacuo to give the crude product, which was purified bycolumn chromatography (PE) to give3-(2-bromo-4-fluorophenylpropoxy)(tert-butyl)dimethylsilane (19.6 g) asa colorless oil. MS (ESI): m/z 329 (M+H)⁺.

(b) (2S)-tert-butyl2-((2-(3-(tert-butyldimethylsilyloxy)propyl)-5-fluorophenyl)(hydroxy)-methyl)pyrrolidine-1-carboxylate

To a solution of(3-(2-bromo-4-fluorophenyl)propoxy)(tert-butyl)dimethylsilane (6.95 g,20 mmol) in toluene (60 mL) at −78° C. was added n-BuLi (16 mL, 40mmol). After the mixture was stirred at this temperature for 2 h,(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (5.98 g, 30 mmol) wasadded. The mixture was stirred at this temperature for an additional 3h, and quenched with ammonium chloride (aq. sat. 20 mL). The mixture wasextracted with ethyl acetate (20 mL×2), and the organic phase was washedwith saturated aqueous brine (2×20 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The crude was purified by silica gel chromatography (petro ether:ethylacetate=10:1) to give the desired product (3.2 g) as orange oil.

(c). (2S)-tert-butyl2-((5-fluoro-2-(3-hydroxypropyl)phenyl)(hydroxy)-methyl)pyrrolidine-1-carboxylate

To a solution of (2S)-tert-butyl2-((2-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate(3.2 g, 6.84 mmol) in THF (30 mL) was added TBAF (3.58 g, 13.68 mmol).After the mixture was stirred at room temperature for 3 h, the solventwas evaporated in vacuo to give an oil. EtOAc (150 mL) was added to thereaction vessel and the resulting biphasic mixture was transferred to aseparatory funnel. The layers were separated and the organic phase waswashed with water (3×100 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the crude product,which was used in the next step without further purification. MS (ESI)m/z 354 (M+H)

(d). (2S)-2-(8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine

To a solution of (2S)-tert-butyl2-((5-fluoro-2-(3-hydroxypropyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (2 g, 5.66 mmol) in DCM (10 mL) wasadded trimethylsilyl trifluoromethanesulfonate (3.77 g, 16.98 mmol).After the mixture was stirred at room temperature for 3 h, solvent wasevaporated in vacuo to give the crude product. To the crude product,water (50 mL) was added. The mixture was washed with PE (50 mL×3). NaOH(aq. 40%) was added to the mixture until basic (pH>9). The mixture wasthen extracted with DCM (100 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to givethe crude product as a mixture of diastereoisomers. MS (ESI) m/z 236(M+H)+.

(e).(S)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-106) and (S)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-107)

(S)-2-(8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine fromprevious step (800 mg) was purified by Prep-HPLC to give(S)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-106, 200 mg) and(S)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl) pyrrolidine(I-107, 250 mg).

(S)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-106): MS (ESI) m/z 236 (M+H)⁺. ¹H NMR (HCl salt, 400 MHz, MeOD) δ7.26˜7.23 (m, 1H), 7.02˜6.95 (m, 2H), 5.06 (m, 1H), 4.28˜4.20 (m, 2H),3.93˜3.86 (m, 1H), 3.44˜3.31 (m, 2H), 3.17˜3.10 (m, 1H), 2.97˜2.91 (m,1H), 2.24˜2.05 (m, 4H), 1.98˜1.92 (m, 2H).

(S)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl) pyrrolidine(I-107): MS (ESI) m/z 236 (M+H)⁺. ¹H NMR (HCl salt, 400 MHz, MeOD) δ7.28˜7.25 (m, 1H), 7.05˜6.78 (m, 2H), 4.85 (d, J=8.8 Hz, 1H), 4.28˜4.15(m, 2H), 4.06˜3.99 (m, 1H), 3.45˜3.39 (m, 2H), 3.1˜3.04 (m, 1H),2.31˜2.11 (m, 3H), 1.86˜1.81 (m, 3H)

Example 1.4.2.(S)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-97) and(S)-2-((R)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-98)

(S)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-97) and(S)-2-((R)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-98) wereprepared using a procedure analogous to that described in Example 1.4.1,but using 3-(2-bromophenyl)propan-1-ol in place of3-(2-bromo-4-fluorophenyl)propan-1-ol.

(S)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-97): MS(ESI): m/z 218 [M+H]⁺, ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.35-7.11 (m,4H), 4.83 (d, J=8.6 Hz, 1H), 4.31-4.13 (m, 2H), 4.02-3.95 (m, 1H),3.47-3.34 (m, 2H), 3.17-3.06 (m, 2H), 2.37-2.21 (m, 1H), 2.19-2.06 (m,2H), 1.96-1.74 (m, 3H).

(S)-2-((R)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-98): MS(ESI): m/z 218 [M+H]⁺, ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.36-7.12 (m,4H), 5.08 (d, J=3.4 Hz, 1H), 4.37-4.18 (m, 2H), 4.02-3.81 (m, 1H),3.54-3.38 (m, 2H), 3.22-3.16 (m, 1H), 3.10-2.92 (m, 1H), 2.32-1.87 (m,6H).

Example 1.4.3.(R)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-99) and(R)-2-((R)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-100)

(R)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-99) and(R)-2-((R)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-100)were prepared using a procedure analogous to that described in Example1.4.1, but using 3-(2-bromophenyl)propan-1-ol in place of3-(2-bromo-4-fluorophenyl)propan-1-ol and (R)-tert-butyl2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-99): MS(ESI): m/z 218 [M+H]⁺, ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.30-7.16 (m,4H), 5.07 (d, J=3.5 Hz, 1H), 4.25 (tt, J=8.5, 3.2 Hz, 2H), 3.90 (ddd,J=12.2, 10.5, 4.4 Hz, 1H), 3.47-3.33 (m, 2H), 3.15 (ddd, J=14.4, 8.7,3.4 Hz, 1H), 2.97 (ddd, J=14.5, 8.5, 3.2 Hz, 1H), 2.28-2.04 (m, 4H),2.02-1.82 (m, 2H).

(R)-2-((R)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-100): MS(ESI): m/z 218 [M+H]⁺, ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.37-7.12 (m,4H), 4.85 (t, J=6.4 Hz, 1H), 4.34-4.12 (m, 2H), 3.99 (ddd, J=12.2, 10.7,4.2 Hz, 1H), 3.40 (ddd, J=24.0, 12.0, 7.5 Hz, 2H), 3.21-2.95 (m, 2H),2.27 (dtd, J=12.6, 7.8, 4.8 Hz, 1H), 2.20-2.05 (m, 2H), 1.96-1.72 (m,3H).

Example 1.4.4.(R)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-108) and(R)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-109)

(R)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-108) and(R)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-109) were prepared using a procedure analogous to that described inExample 1.4.1, but using (R)-tert-butyl2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-108): MS (ESI): m/z 236 [M+H]⁺, ¹HNMR (HCl salt, 400 MHz, MeOD): δ7.08˜7.04 (m, 1H), 6.92˜6.89 (m, 1H), 6.80˜6.75 (m, 1H), 4.36 (m, 1H),4.09 (m, 1H), 3.81 (m, 1H), 3.51 (m, 1H), 2.94 (m, 2H), 2.80 (m, 2H),1.88 (m, 1H), 1.73 (m, 2H), 1.64 (m, 2H), 1.40 (m, 1H).

(R)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-109): MS (ESI): m/z 236 [M+H]⁺, ¹HNMR (HCl salt, 400 MHz, MeOD): δ7.27˜7.23 (m, 1H), 7.01˜6.98 (m, 2H), 5.06 (d, J=3.6 Hz, 1H), 4.24 (m,2H), 3.92 (m, 1H), 3.40 (m, 2H), 3.14 (m, 1H), 2.97 (m, 1H), 2.11 (m,4H), 1.93 (m, 2H).

Example 1.4.5.(S)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-110) and(S)-2-((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-111)

(S)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-110) and(S)-2-((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-111) were prepared using a procedure analogous to that described inExample 1.4.1, but using 3-(2-bromo-5-fluorophenyl)propan-1-ol in placeof 3-(2-bromo-4-fluorophenyl)propan-1-ol.

(S)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-110): MS (ESI): m/z 236 [M+H]⁺, ¹HNMR (400 MHz, CDCl₃): δ 7.24 (dd,J¹=5.2 Hz, J²=8.0 Hz, 1H), 6.91-6.83 (m, 2H), 5.53 (brs, 1H), 4.55 (d,J=8.0 Hz, 1H), 4.25-4.20 (m, 1H), 3.94-3.87 (td, J¹=3.2 Hz, J²=12.0 Hz,1H), 3.85-3.79 (q, J=8.0 Hz, 1H), 3.27-3.21 (m, 1H), 3.12-3.01 (m, 2H),2.97-2.91 (m, 1H), 2.06-1.72 (m, 5H), 1.66-1.54 (m, 1H).

(S)-2-((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-111): MS (ESI): m/z 236 [M+H]⁺, ¹HNMR (400 MHz, CDCl₃): δ 7.25-7.22(dd, J¹=6.0 Hz, J²=8.0 Hz, 1H), 6.90-6.84 (m, 2H), 4.52 (d, J=6.4 Hz,1H), 4.24-4.19 (m, 1H), 3.85-3.79 (td, J¹=3.6 Hz, J²=11.2 Hz, 1H),3.61-3.55 (m, 1H), 3.10-2.86 (m, 4H), 2.21 (brs, 1H), 2.06-1.75 (m, 6H).

Example 1.4.6.(R)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-112) and(R)-2-((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-113)

(R)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-112) and(R)-2-((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-113) were prepared using a procedure analogous to that described inExample 1.4.1, but using 3-(2-bromo-5-fluorophenyl)propan-1-ol in placeof 3-(2-bromo-4-fluorophenyl)propan-1-ol and (R)-tert-butyl2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-112): MS (ESI): m/z 236 [M+H]⁺, ¹HNMR (HCl salt, 400 MHz, MeOD): δ7.24-7.21 (dd, J¹=5.6 Hz, J²=8.4 Hz, 1H), 7.04-6.95 (m, 2H), 5.03 (d,J=3.2 Hz, 1H), 4.29-4.20 (m, 2H), 3.93-3.86 (m, 1H), 3.44-3.33 (m, 2H),3.16-3.10 (m, 1H), 3.01-2.95 (m, 1H), 2.27-2.06 (m, 4H), 1.97-1.85 (m,2H).

(R)-2-((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-113): MS (ESI): m/z 236 [M+H]⁺, ¹HNMR (400 MHz, CDCl₃): δ 7.24 (dd,J¹=5.6 Hz, J²=8.0 Hz, 1H), 6.91-6.83 (m, 2H), 5.57 (brs, 1H), 4.55 (d,J=8.0 Hz, 1H), 4.25-4.20 (m, 1H), 3.94-3.79 (m, 2H), 3.27-3.21 (m, 1H),3.12-3.01 (m, 2H), 2.97-2.91 (m, 1H), 2.06-1.72 (m, 5H), 1.66-1.54 (m,1H).

Example 1.4.7.(S)-2-((R)-9-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-105)

(S)-2-((R)-9-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-105) was prepared using a procedure analogous to that described inExample 1.4.1, but using 3-(2-bromo-3-fluorophenyl)propan-1-ol in placeof 3-(2-bromo-4-fluorophenyl)propan-1-ol. ESI: m/z=236 (M+H)⁺. ¹H NMR(HCl salt, 400 MHz, MeOD): δ 7.33˜7.28 (m, 1H), 7.06˜7.01 (m, 2H), 5.37(s, 1H), 4.20˜4.15 (m, 1H), 4.09˜4.06 (m, 1H), 3.68˜3.60 (m, 1H),3.46˜3.35 (m, 3H), 2.69˜2.66 (m, 1H), 2.26˜2.15 (m, 3H), 2.01˜1.96 (m,1H), 1.89˜1.84 (m, 2H).

Example 1.4.8.((S)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-101) and(S)-2-((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-102)

(S)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-101) and(S)-2-((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-102) were prepared using a procedure analogous to that described inExample 1.4.1, but using 3-(2-bromo-3-methylphenyl)propan-1-ol in placeof 3-(2-bromo-4-fluorophenyl)propan-1-ol.

(S)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-101): (ESI) m/z: 232[M+H]⁺. ¹HNMR (400 MHz, CDCl₃): δ 7.11-7.07 (t,J=7.6 Hz, 1H), 7.04-7.02 (d, J=7.2 Hz, 1H), 6.97-6.95 (d, J=7.6 Hz, 1H),5.06-5.04 (d, J=6.0 Hz, 1H), 4.02-3.96 (m, 1H), 3.61-3.46 (m, 3H),3.17-3.11 (m, 1H), 2.90-2.83 (m, 1H), 2.56-2.51 (m, 1H), 2.34 (s, 3H),2.10-2.05 (m, 1H), 2.04 (brs, 1H), 1.84-1.57 (m, 5H).

(S)-2-((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-102): (ESI) m/z: 232[M+H]⁺. ¹HNMR (400 MHz, MeOD): δ 7.18-7.15 (t,J=7.6 Hz, 1H), 7.12-7.10 (d, J=6.8 Hz, 1H), 7.04-7.02 (d, J=7.2 Hz, 1H),5.39-5.38 (d, J=3.2 Hz, 1H), 4.14-4.08 (m, 1H), 3.99-3.94 (m, 1H),3.61-3.35 (m, 4H), 2.58-2.53 (m, 1H), 2.37 (s, 3H), 2.35-2.10 (m, 3H),2.04-1.92 (m, 1H), 1.83-1.72 (m, 2H).

Example 1.4.9.(R)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-104) and(R)-2-((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-103)

(R)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-104) and(R)-2-((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-103) were prepared using a procedure analogous to that described inExample 1.4.1, but using 3-(2-bromo-3-methylphenyl)propan-1-ol in placeof 3-(2-bromo-4-fluorophenyl)propan-1-ol and (R)-tert-butyl2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-104): (ESI) m/z: 232[M+H]⁺. ¹HNMR (400 MHz, MeOD): δ 7.18-7.15 (t,J=7.6 Hz, 1H), 7.12-7.10 (d, J=6.8 Hz, 1H), 7.04-7.02 (d, J=7.2 Hz, 1H),5.39-5.38 (d, J=3.2 Hz, 1H), 4.14-4.08 (m, 1H), 3.99-3.94 (m, 1H),3.61-3.35 (m, 4H), 2.58-2.53 (m, 1H), 2.37 (s, 3H), 2.35-2.10 (m, 3H),2.04-1.92 (m, 1H), 1.83-1.72 (m, 2H).

(R)-2-((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine(I-103): (ESI) m/z: 232 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): δ 7.11-7.07 (t,J=7.6 Hz, 1H), 7.04-7.02 (d, J=7.2 Hz, 1H), 6.97-6.95 (d, J=7.6 Hz, 1H),5.06-5.04 (d, J=6.0 Hz, 1H), 4.02-3.96 (m, 1H), 3.61-3.46 (m, 3H),3.17-3.11 (m, 1H), 2.90-2.83 (m, 1H), 2.56-2.51 (m, 1H), 2.34 (s, 3H),2.17 (brs, 1H), 2.10-2.05 (m, 1H), 1.84-1.57 (m, 5H).

Example 1.5. Procedure E. Certain Provided Compounds were Made Followinga Procedure Exemplified by Example 1.5.1 Example 1.5.1.(S)-2-((S)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-65) and(S)-2-((R)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-66)

(a). 1-(2-bromophenyl)-2-methylpropan-2-ol

To a solution of methyl 2-(2-bromophenyl)acetate (5 g, 21.83 mmol) inTHF (100 mL) at −78° C. was added dropwise methylmagnesium bromide(21.83 mL, 3M in Et₂O). The mixture was stirred at this temperature for16 h, then gradually warmed to room temperature. The mixture was thencooled to 0° C., and saturated aqueous ammonium chloride (2 mL) wasadded. After 10 minutes, the mixture was extracted with EtOAc (3×120mL). The organic layers were combined, dried, filtered and concentrated.The crude material was purified by silica gel chromatography(PE:EtOAc=20:1) to yield 1-(2-bromophenyl)-2-methylpropan-2-ol (4.5 g)as a colorless oil.

(b). (2S)-tert-butyl2-(hydroxy(2-(2-hydroxy-2-methylpropyl)phenyl)methyl)pyrrolidine-1-carboxylate

To a solution of 1-(2-bromophenyl)-2-methylpropan-2-ol (4.5 g, 15.71mmol) in toluene (80 mL) was added butyllithium (2.21 g, 34.56 mmol) at−78° C. After stirring at −78° C. for 1 h, (S)-tert-butyl2-formylpyrrolidine-1-carboxylate (4.07 g, 20.42 mmol) in toluene (20mL) was added. The mixture was stirred at −78° C. for an additional 3 h.The mixture was poured into iced water and extracted with EtOAc (3×100mL). The organic layers were combined, dried over Na₂SO₄, filtered andconcentrated. The residue was then purified by column chromatography togive the crude product (0.99 g). ESI: m/z=350 (M+H⁺).

(c). (2S)-2-(3,3-dimethylisochroman-1-yl)pyrrolidine

To a solution of (2S)-tert-butyl2-(hydroxy(2-(2-hydroxy-2-methylpropyl)phenyl)methyl)pyrrolidine-1-carboxylate (4 g, 5.95 mmol) in toluene (100 mL)was added 85% phosphoric acid (10 mL). The reaction mixture was heatedat 110° C. for 16 h. Toluene was removed by distillation and to theresulting residue was added water (100 mL), and washed with ethylacetate (2×80 mL). The aqueous layer was used for next step withoutfurther purification. ESI: m/z=232 (M+H⁺).

(d). (2S)-tert-butyl 2-(3,3-dimethylisochroman-1-yl)pyrrolidine-1-carboxylate

To a solution of (2S)-2-(3,3-dimethylisochroman-1-yl)pyrrolidine inwater from previous step was added NaOH (0.31 g, 7.86 mmol) anddi-tert-butyl dicarbonate (1.72 g, 7.86 mmol) at 0° C. The mixture wasstirred at room temperature for 2 h and then was extracted with EtOAc(3×100 mL). The organic layers were combined, washed with brine (2×60mL), dried over Na₂SO₄, filtered and concentrated to give the residue,which was purified by prep-HPLC to give (2S)-tert-butyl2-(3,3-dimethylisochroman-1-yl)pyrrolidine-1-carboxylate 780 mg as ayellow oil. ESI: m/z=332 (M+H⁺).

(e). (S)-2-((S)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-65) and(S)-2-((R)-3,3-dimethyl-isochroman-1-yl)pyrrolidine (I-66)

To a solution of (2S)-tert-butyl2-(3,3-dimethylisochroman-1-yl)pyrrolidine-1-carboxylate (780 mg, 2.35mmol) in ethyl acetate (20 mL) was added HCl/dioxane (1.44 g, 40 mmol).The reaction mixture was stirred at room temperature for 4 h. Uponcompletion, the mixture was concentrated and the residue separated byPREP-HPLC to give two diastereoisomers, which were each purified againby chiral HPLC: AS-H (250*4.6 mm 5 μm) and mobile phase: MeOH (0.1% DEA)to give (S)-2-((S)-3,3-dimethylisochroman-1-yl) pyrrolidine (I-65) (120mg) and (S)-2-((R)-3,3-dimethylisochromanl-yl) pyrrolidine (I-66) (80mg).

(S)-2-((S)-3,3-dimethylisochroman-1-yl) pyrrolidine (I-65): ESI: m/z=232(M+H⁺). ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.28-7.37 (m, 3H), 7.19-7.21(m, 1H), 5.03 (s, 1H), 4.23-4.28 (m, 1H), 3.30-3.33 (m, 2H), 3.06-3.10(J=15.6 Hz, d, 1H), 2.64-2.68 (J=16 Hz, d, 1H), 2.26-2.32 (m, 2H),2.02-2.18 (m, 2H), 1.43 (s, 3H), 1.20 (s, 3H).

(S)-2-((R)-3,3-dimethylisochromanl-yl) pyrrolidine (I-66): ESI: m/z=232(M+H⁺). ¹HNMR (400 MHz, MeOD): δ 7.17-7.28 (m, 4H), 5.23 (s, 1H),4.31-4.35 (m, 1H), 3.32-3.37 (m, 2H), 2.89-2.94 (J=16.4 Hz, d, 1H),2.65-2.69 (J=16 Hz, d, 1H), 2.03-2.08 (m, 1H), 1.93-1.98 (m, 1H),1.70-1.76 (m, 2H), 1.44 (s, 3H), 1.21 (s, 3H).

Example 1.5.2. ((R)-2-((S)-3,3-dimethylisochroman-1-yl)pyrrolidine(I-67) and (R)-2-((R)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-68)

(R)-2-((S)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-67) and(R)-2-((R)-3,3-dimethyl-isochroman-1-yl)pyrrolidine (I-68) were preparedusing a procedure analogous to that described in Example 1.5.1, butusing (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-67): ESI: m/z=232(M+H⁺). ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.14-7.25 (m, 4H), 5.15 (s,1H), 4.01-4.06 (m, 1H), 3.24-3.32 (m, 1H), 3.10-3.16 (m, 1H), 2.87-2.91(J=15.6 Hz, d, 1H), 2.62-2.66 (J=15.6 Hz, d, 1H), 1.83-1.95 (m, 2H),1.56-1.67 (m, 2H), 1.41 (s, 3H), 1.19 (s, 3H).

(R)-2-((R)-3,3-dimethyl-isochroman-1-yl)pyrrolidine (I-68): ESI: m/z=232(M+H⁺). ¹HNMR (400 MHz, MeOD): δ 7.28-7.36 (m, 3H), 7.19-7.21 (m, 1H),5.03 (s, 1H), 4.23-4.27 (m, 1H), 3.23-3.32 (m, 2H), 3.05-3.09 (J=16 Hz,d, 1H), 2.64-2.68 (J=16 Hz, d, 1H), 2.26-2.32 (m, 2H), 2.04-2.17 (m,2H), 1.44 (s, 3H), 1.20 (s, 3H).

Example 1.6. General Procedure F. Certain Provided Compounds were MadeFollowing a Procedure Exemplified by Example 1.6.1 Example 1.6.1.(R)-2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I-62) and(R)-2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I-61)

(a). (R)-(9H-fluoren-9-yl)methyl2-(hydroxymethyl)-4,4-dimethyl-pyrrolidine-1-carboxylate

To a solution of (R)-(4,4-dimethylpyrrolidin-2-yl)methanol (3.2 g, 24.77mmole) in THF (100 mL) and water (30 mL) was added Na₂CO₃ (7.87 g, 74.30mmole) as solid. The suspension was cooled to 0° C. and Fmoc-Cl (9.61 g,37.15 mmole) was added dropwise. After the addition, the cold bath wasremoved and the reaction mixture was stirred at room temperature for 2h. Water (200 mL) was added. The resulting solid was filtered offthrough a pad of Celite. The filtrate was separated and extracted withethyl acetate (200 mL×2). The combined organic layers were washed withdilute brine (50 mL×2), dried over sodium sulfate, filtered andconcentrated to give a crude product which was purified through columnchromatography (EtOAc/PE=1:10) to give the product (7.1 g) as acolorless oil. LC/MS (ESI+): m/z=352.3 (M+H).

(b). (R)-(9H-fluoren-9-yl)methyl2-formyl-4,4-dimethylpyrrolidine-1-carboxylate

To a solution of (R)-(9H-fluoren-9-yl)methyl2-(hydroxymethyl)-4,4-dimethylpyrrolidine-1-carboxylate (7.1 g, 20.20mmole) in DCM (80 mL) was added Dess-Martin reagent (25.71 g, 60.61mmole) slowly at 0° C. The mixture was stirred at room temperatureovernight and the reaction was then quenched with NaHCO₃ (sat. aq. 100mL). The resulting mixture was then extracted with DCM (200 mL×2). Thecombined organic layers were washed with brine (50 mL×2), dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified by column chromatography (EtOAc/PE=1:10) to give the product(3.25 g) as a colorless oil. LC/MS (ESI+): m/z=351.2 (M+H).

(c). (R)-(9H-fluoren-9-yl)methyl2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine-1-carboxylate and(R)-(9H-fluoren-9-yl)methyl2-((R)-isochroman-1-yl)-4,4-dimethyl-pyrrolidine-1-carboxylate

To a solution of (R)-(9H-fluoren-9-yl)methyl2-formyl-4,4-dimethylpyrrolidine-1-carboxylate (3.25 g, 9.30 mmole) inDCM (16 mL) was added 2-phenylethanol (1.136 g, 9.30 mmole) and TfOH (2mL) at 0° C. The mixture was stirred at room temperature for 1 h. SolidNa₂CO₃ was added to adjust the pH to 7-8, and EtOAc (300 mL) was added.The mixture was washed with water (100 mL×2), sat.NaCl (100 mL×2), driedand concentrated to give the crude product, which was purified byPrep-HPLC to give (R)-(9H-fluoren-9-yl)methyl2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine-1-carboxylate (1.02 g)and (R)-(9H-fluoren-9-yl)methyl2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine-1-carboxylate(1-11) (805mg). LC-MS: 454.1 (M+H).

(d). (R)-2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine

To a solution of (R)-(9H-fluoren-9-yl)methyl2-((S)-isochroman-1-yl)-4,4-dimethyl-pyrrolidine-1-carboxylate (1.02 g)in DMF (8 mL) was added morpholine (8 mL). The mixture was stirred atroom temperature for 2 h. The resulting solid was filtered off. To thefiltrate was added EtOAc (200 mL) and the mixture was then washed withwater (30 mL×3), sat. NaCl (30 mL×3), dried, and concentrated to give aresidue, which was purified by prep-HPLC to give the product (300 mg).LC-MS: 232.2 (M+H). ¹H NMR (CDCl₃, 400 MHz): 7.28-7.10 (m, 4H), 4.96 (d,J=3.2 Hz, 1H), 4.25-4.20 (m, 1H), 3.80-3.72 (m, 2H), 3.10-3.02 (m, 1H),2.80 (d, J=10.8 Hz, 1H), 2.70-2.61 (m, 2H), 1.40-1.26 (m, 1H), 1.24-1.19(m, 1H), 1.03 (s, 3H), 1.01 (s, 3H).

(e). (R)-2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine

To a solution of (R)-(9H-fluoren-9-yl)methyl2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine-1-carboxylate (805 mg)in DMF (8 mL) was added morpholine (8 mL). The mixture was stirred atroom temperature for 2 h. The resulting solid was filtered off and tothe filtrate was added EtOAc (200 mL). The mixture was washed with water(30 mL×3), sat. NaCl (30 mL×3), dried and concentrated to give aresidue, which was purified by prep-HPLC to give the product (242 mg).LC-MS: 232.2 (M+H). ¹H NMR (CDCl3,400 MHz): 7.28-7.10 (m, 4H), 4.71 (d,J=4.0 Hz, 1H), 4.25-4.20 (m, 1H), 3.80-3.72 (m, 2H), 3.07-2.98 (m, 1H),2.80 (d, J=10.8 Hz, 1H), 2.70-2.61 (m, 2H), 1.79-1.74 (m, 1H), 1.68-1.63(m, 1H), 1.10 (s, 3H), 1.08 (s, 3H).

Example 1.6.2. (S)-2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine(I-60) and (S)-2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I-59)

(S)-2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I-60)and(S)-2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I-59) wereprepared using a procedure analogous to that described in Example 1.6.1,but using (S)-(4,4-dimethylpyrrolidin-2-yl)methanol in place of(R)-(4,4-dimethylpyrrolidin-2-yl)methanol.

(S)-2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I-60): LC-MS: 232.2(M+H). ¹HNMR (HCl salt, DMSO-d6, 400 MHz): 9.62 (s, 1H), 8.45 (s, 1H),7.33-7.18 (m, 4H), 4.90 (s, 1H), 4.32-4.28 (m, 1H), 4.27-4.18 (m, 1H),3.78-3.73 (m, 1H), 3.17-3.04 (m, 1H), 2.83-2.66 (m, 2H), 2.58-2.53 (m,1H), 2.12-1.93 (m, 1H), 1.89-1.78 (m, 1H), 1.17 (s, 3H), 1.12 (s, 3H).

(S)-2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I-59): LC-MS: 232.2(M+H). ¹HNMR (HCl salt, DMSO-d6,400 MHz): 9.62 (s, 1H), 8.45 (s, 1H),7.33-7.18 (m, 4H), 4.90 (s, 1H), 4.32-4.28 (m, 1H), 4.27-4.18 (m, 1H),3.78-3.73 (m, 1H), 3.17-3.04 (m, 1H), 2.83-2.66 (m, 2H), 2.58-2.53 (m,1H), 2.12-1.93 (m, 1H), 1.89-1.78 (m, 1H), 1.17 (s, 3H), 1.12 (s, 3H).

Example 1.7. Procedure G. Certain Provided Compounds were Made Followinga Procedure Exemplified by Example 1.7.1 Example 1.7.1.(R)-3-(isochroman-1-yl)azetidine (I-114) and(S)-3-(isochroman-1-yl)azetidine (I-115)

(a). tert-butyl3-(2-(2-(tert-butyldimethylsilyloxy)ethyl)benzoyl)azetidine-1-carboxylate

To a stirred solution of (2-bromophenethoxy)(tert-butyl)dimethylsilane(15.77 g, 50 mmol) in dry THF (200 mL) was added dropwise n-Butyllithium (25 mL, 60 mmol, 2.4 M solution in hexane) at −78° C. undernitrogen, and the reaction mixture was stirred at this temperature for 1h. To the reaction mixture, a solution of tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (12.2 g, 50 mmol) in dry THF (50 mL)was added dropwise. The reaction mixture was stirred at −78° C. for 1 hand then quenched by addition of a saturated aqueous NH₄Cl solution (50mL). The aqueous phase was extracted with ethyl acetate and the combinedorganic phase were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give a residue, which waspurified by column chromatography (petroleum ether/ethyl acetate: 5/1)to afford butyldimethylsilyl)oxy)ethyl)benzoyl)azetidine-1-carboxylate(13.3 g) as colorless oil.

(b). tert-butyl3-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)(hydroxy)methyl)-azetidine-1-carboxylate

To a solution of tert-butyl3-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzoyl)azetidine-1-carboxylate(13.22 g, 31.5 mmol) in methanol (157 mL) was added sodium borohydride(1.79 g, 47.25 mmol) slowly at 0° C. Then mixture was stirred at roomtemperature for 1 h. The solvent was removed and the residue was addedwater (100 mL) and ethyl acetate (100 mL). The resulting biphasicmixture was transferred to a separatory funnel. The layers wereseparated and the organic phase was washed with brine (50 mL), driedover anhydrous sodium sulfate, filtered, concentrated to give a residue,which was purified by column chromatography (ethyl acetate/petroleumether=1:5) to give the product (13 g) as a colorless oil.

(c). (tert-butyl3-(hydroxy(2-(2-hydroxyethyl)phenyl)methyl)azetidine-1-carboxylate

To a solution of tert-butyl3-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)(hydroxy)methyl)azetidine-1-carboxylate (6.5 g, 15.42 mmol) intetrahydrofuran (75 mL) was added tetrabutylammonium fluoride (4.03 g,15.42 mmol) at 0° C. The mixture was stirred at room temperatureovernight and solvent removed. The residue was diluted with EtOAc (500mL), washed with brine (4×50 mL), dried over sodium sulfate andconcentrated. The crude product was purified by silica gelchromatography (ethyl acetate/petroleum ether=1:5) to give the productas a colorless oil (4.7 g).

(d). (R)-tert-butyl 3-(isochroman-1-yl)azetidine-1-carboxylate and(S)-tert-butyl 3-(isochroman-1-yl)azetidine-1-carboxylate

To a solution of tert-butyl3-(hydroxy(2-(2-hydroxyethyl)phenyl)methyl)azetidine-1-carboxylate (4.5g, 14.64 mmol) in toluene (100 mL) was added n-butyllithium (6.89 mL,16.54 mmol) at 0° C. After 30 min, 4-methyl-benzenesulfonyl chloride(3.15 g, 16.54 mmol) was added to the mixture. The mixture was stirredat this temperature for another 1 h and n-butyllithium (9.15 mL, 21.96mmol) was added. The reaction mixture was stirred at 40° C. for 16 h andthen poured into iced-water, and extracted with EtOAc (3×100 mL). Thecombined organic layers were washed with brine (2×100 mL), dried overNa₂SO₄, filtered and concentrated to give a residue, which was purifiedby pre-HPLC to give the racemic mixture of tert-butyl3-(isochroman-1-yl)azetidine-1-carboxylate as yellow oi (1.5 g). Theracemate was then separated by chiral HPLC, column: OZ-H (250*4.6 mm 5μm) and mobile phase: MeOH (0.1% DEA) to give(R)-tert-butyl-3-(isochroman-1-yl)azetidine-1-carboxylate and(S)-tert-butyl-3-(isochroman-1-yl)azetidine-1-carboxylate as colorlessoil.

(e). (R)-3-(isochroman-1-yl)azetidine (I-114)

To a solution of (R)-tert-butyl3-(isochroman-1-yl)azetidine-1-carboxylate (0.4 g, 1.38 mmol) in DCM (10mL) was added 2,2,2-trifluoroacetic acid (2 mL) dropwise. The mixturewas stirred at room temperature for 2 h and solvent was removed. Theresidue was dissolved in water (15 mL), followed by addition of aqueousNH₄OH. The resulting mixture was extracted with DCM (20 mL×5). Theorganic phase was combined, dried over Na₂SO₄, filtered, andconcentrated to give (R)-3-(isochroman-1-yl)azetidine (I-114) (0.25 g)as a yellow oil. MS (ESI): m/z 190 [M+H]⁺, ¹H NMR (HCl salt, 400 MHz,MeOD) δ 7.26-7.17 (m, 3H), 7.13-7.06 (m, 1H), 4.94 (s, 1H), 4.38 (m,1H), 4.34-4.22 (m, 2H), 3.98-3.82 (m, 2H), 3.77 (dd, J=10.4, 6.3 Hz,1H), 3.69-3.55 (m, 1H), 3.17 (m, 1H), 2.79-2.67 (m, 1H).

(f). (S)-3-(isochroman-1-yl)azetidine (I-115)

To a solution of (S)-tert-butyl3-(isochroman-1-yl)azetidine-1-carboxylate (0.45 g, 1.56 mmol) in DCM(10 mL) was added 2,2,2-trifluoroacetic acid (2 mL) dropwise. Themixture was stirred at room temperature for 2 h, and solvent wasremoved. The residue was dissolved in water (15 mL), followed byaddition of aqueous NH₄OH. The resulting mixture was extracted with DCM(20 mL×5). The organic phase was combined, dried over Na₂SO₄, andconcentrated to give (S)-3-(isochroman-1-yl)azetidine (0.27 gas a yellowoil. MS (ESI): m/z 190 [M+H]⁺, ¹H NMR (HCl salt, 400 MHz, MeOD) δ7.15-7.04 (m, 3H), 7.00-6.92 (m, 1H), 4.82 (s, 1H), 4.26 (m, 1H), 4.16(p, J=10.2 Hz, 2H), 3.76 (m, 2H), 3.65 (dd, J=10.3, 6.4 Hz, 1H),3.55-3.44 (m, 1H), 3.05 (m, 1H), 2.61 (d, J=16.5 Hz, 1H).

Example 1.7.2. ((R)-3-(7-methylisochroman-1-yl)azetidine (I-116) and(S)-3-(7-methylisochroman-1-yl)azetidine (I-117)

(R)-3-(7-methylisochroman-1-yl)azetidine (I-116) and(S)-3-(7-methylisochroman-1-yl)azetidine (I-117) were prepared using aprocedure analogous to that described in Example 1.7.1, but using(2-bromo-4-methylphenethoxy)(tert-butyl)dimethylsilane in place of(2-bromophenethoxy)(tert-butyl)dimethylsilane.

(R)-3-(7-methylisochroman-1-yl)azetidine (I-116): MS m/z 204 [M+H]⁺, ¹HNMR (HCl salt, 400 MHz, MeOD) δ 7.06 (M, 2H), 6.91 (s, 1H), 4.90 (s,1H), 4.36 (M, 1H), 4.33-4.20 (m, 2H), 3.98-3.89 (m, 1H), 3.88-3.72 (m,2H), 3.67-3.54 (m, 1H), 3.19-3.04 (m, 1H), 2.67 (d, J=15.5 Hz, 1H), 2.30(s, 3H).

(S)-3-(7-methylisochroman-1-yl)azetidine (I-117): MS m/z 204 [M+H]⁺, ¹HNMR (HCl salt, 400 MHz, MeOD) δ 7.05 (m, 2H), 6.91 (s, 1H), 4.89 (s,1H), 4.36 (m 1H), 4.27 (dd, J=15.6, 7.1 Hz, 2H), 3.93 (t, J=9.6 Hz, 1H),3.89-3.72 (m, 2H), 3.66-3.54 (m, 1H), 3.20-3.05 (m, 1H), 2.67 (d, J=15.3Hz, 1H), 2.30 (s, 3H).

Example 1.8. Procedure H. Certain Provided Compounds were Made Followinga Procedure Exemplified by Example 1.8.1 Example 1.8.1.(S)-1-((S)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-43) and(R)-1-((S)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-44)

(a). (2S)-tert-butyl 2-(6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate

(2S)-tert-butyl 2-(6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate wasprepared using General Procedure A starting from2-(3-bromophenyl)ethanol and (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(b). (2S)-tert-butyl 2-(6-cyanoisochroman-1-yl)pyrrolidine-1-carboxylate

A mixture of (2S)-tert-butyl2-(6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate (3.93 g, 10.31mmol), dicyanozinc (2.42 g, 20.63 mmol),tetrakis(triphenylphosphine)palladium (1.19 g, 1.03 mmol) in DMF (20 mL)was stirred at 120° C. in microwave reactor for 3 h under nitrogenatmosphere. Upon completion, the mixture was filtered and the filtratewas purified by flash chromatography to afford the product (2.2 g) as alight yellow oil.

(c). (S)-1-((S)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-43) and(R)-1-((S)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-44)

(2S)-tert-butyl 2-(6-cyanoisochroman-1-yl)pyrrolidine-1-carboxylate (2.1g, 6.39 mmol) was stirred in HCl/dioxane (3 M) (20 mL) at roomtemperature for about 2 h. To the mixture was added NH₄OH (aq.) till pH8˜9 and the mixture was concentrated in vacuo. The crude product waspurified by Prep-HPLC to give the two diastereoisomers, which then wereeach separately purified by chiral separation using column: AY-H(250*4.6 mm 5 μm); Moblie Phase: n-Hexane (0.1% DEA):EtOH (0.1%DEA)=80:20, followed by another chiral separation using column: OJ-H4.6*250 mm 5 μm, Moblie Phase: MeOH (0.1% DEA), to afford 1-43 and 1-44.MS (ESI) m/z 229.1 (M+H)⁺.

(S)-1-((S)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-43): MS (ESI)m/z 229.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.49˜7.40 (m, 3H), 4.79 (s,1H), 4.27˜4.22 (m, 1H), 3.78˜3.72 (m, 1H), 3.60˜3.55 (m, 1H), 3.11˜3.06(m, 2H), 2.80˜2.67 (m, 2H), 1.95˜1.75 (m, 5H).

(R)-1-((S)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-44): MS (ESI)m/z: 229.1 (M+H)⁺¹. ¹H NMR (HCl salt, 400 MHz, MeOD): δ 7.62 (d, J=7.2Hz, 2H), 7.42 (d, J=8.4 Hz, 1H), 5.27 (s, 1H), 4.42˜4.33 (m, 2H),3.86˜3.79 (m, 1H), 3.38˜3.33 (m, 2H), 3.19˜3.11 (m, 1H), 2.79 (d, J=16.8Hz, 1H), 2.11˜1.93 (m, 2H), 1.79˜1.72 (m, 2H).

Example 1.8.2. (S)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile(I-46) and (R)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-45)

(S)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-46) and(R)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-45) wereprepared using a procedure analogous to that described in Example 1.8.1,but using (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(S)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-46): ESI:m/z=229 (M+H⁺). ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.62-7.63 (J=6.8 Hz,d, 1H), 7.43-7.45 (J=8.4 Hz, d, 1H), 5.28 (s, 1H), 4.33-4.43 (m, 2H),3.79-3.86 (m, 1H), 3.34-3.39 (m, 2H), 3.11-3.19 (m, 1H), 2.64-2.77 (m,2H), 2.77-2.81 (J=16 Hz, d, 1H), 1.94-2.10 (m, 2H), 1.65-1.79 (m, 2H).

(R)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-45): ESI:m/z=229 (M+H⁺). ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.65-7.67 (J=13.2 Hz,d, 1H), 7.53-7.55 (m, 1H), 5.10 (s, 1H), 4.28-4.35 (m, 2H), 3.83-3.89(m, 1H), 3.20-3.30 (m, 3H), 2.77-2.82 (J=17.2 Hz, d, 1H), 2.07-2.35 (m,4H).

Example 1.8.3. (S)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile(I-39) and (R)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-40)

(S)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-39) and(R)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-40) wereprepared using a procedure analogous to that described in Example 1.8.1,but using 2-(4-bromophenyl)ethanol in place of 2-(3-bromophenyl)ethanol.

(S)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-39): MS (ESI):m/z 229 (M+H)⁺. H NMR (HCl salt, 400 MHz, MeOD) δ 7.78 (s, 1H), 7.66(dd, J=7.9, 0.9 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 5.08 (s, 1H), 4.45-4.24(m, 2H), 3.87 (td, J=11.4, 3.3 Hz, 1H), 3.32-3.19 (m, 3H), 2.82 (d,J=17.2 Hz, 1H), 2.41-2.23 (m, 2H), 2.22-1.97 (m, 2H).

(R)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-40): MS (ESI):m/z 229 (M+H)⁺. ¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.72 (d, J=23.5 Hz,1H), 7.62 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 5.25 (s, 1H), 4.43(td, J=8.3, 2.7 Hz, 1H), 4.35 (dd, J=11.4, 6.0 Hz, 1H), 3.83 (td,J=11.7, 2.9 Hz, 1H), 3.38 (ddd, J=11.9, 10.4, 7.6 Hz, 2H), 3.18 (ddd,J=17.8, 11.9, 6.2 Hz, 1H), 2.82 (d, J=17.0 Hz, 1H), 2.14-1.90 (m, 2H),1.87-1.66 (m, 2H).

Example 1.8.4. (S)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile(I-42) and (R)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-41)

(S)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-42) and(R)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-41) wereprepared using a procedure analogous to that described in Example 1.8.1,but using 2-(4-bromophenyl)ethanol in place of 2-(3-bromophenyl) ethanoland (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(S)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-42): MS (ESI)m/z: 229.1 (M+H)⁺¹. ¹H NMR (HCl salt, 400 MHz, MeOD): δ 7.70 (s, 1H),7.62 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 5.25 (s, 1H), 4.46˜4.42(m, 1H), 4.37˜4.11 (m, 1H), 3.87˜3.80 (m, 1H), 3.42˜3.32 (m, 2H),3.22˜3.14 (m, 1H), 2.81 (d, J=16.4 Hz, 1H), 2.10˜1.82 (m, 2H), 1.80˜1.71(m, 2H).

(R)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-41): MS (ESI)m/z: 229.1 (M+H)⁺¹ ¹H NMR (HCl salt, 400 MHz, MeOD): δ 7.78 (s, 1H),7.65 (d, J=7.6 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 5.08 (s, 1H), 4.36˜4.59(m, 2H), 3.90˜3.83 (m, 1H), 3.32˜3.22 (m, 3H), 2.81 (d, J=17.2 Hz, 1H),2.34˜2.03 (m, 4H).

Example 1.9. Procedure I. Certain Provided Compounds were Made Followinga Procedure Exemplified by Example 1.9.1 Example 1.9.1.(S)-3-((S)-isochroman-1-yl)morpholine (I-75) and(S)-3-((R)-isochroman-1-yl)morpholine (I-76)

To a solution of (S)-tert-butyl 3-formylmorpholine-4-carboxylate (0.5 g,2.32 mmol) in DCM (10 mL) was added TMSOTf (2.06 g, 9.28 mmol) and2-phenylethanol (0.28 g, 2.32 mmol). The mixture was stirred at roomtemperature for 2 h, poured into ice-water, extracted with DCM (2×20ml). The combined organic layers were dried, filtered, and solventremoved. The crude was purified by Prep-HPLC to provide(S)-3-((S)-isochroman-1-yl) morpholine (I-75) (70 mg) and(S)-3-((R)-isochroman-1-yl) morpholine (I-76) (50 mg) as orange oil.

(S)-3-((S)-isochroman-1-yl) morpholine (I-75): MS (ESI) m/z 220 (M+H)⁺.¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.33 (m, 3H), 7.26 (m, 1H), 4.99 (s,1H), 4.23 (m, 2H), 3.98 (m, 3H), 3.77 (m, 2H), 3.18 (m, 3H), 2.73 (m,1H).

(S)-3-((R)-isochroman-1-yl) morpholine (I-76): MS (ESI) m/z 220 (M+H)⁺.¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.22 (m, 3H), 7.15 (m, 1H), 4.82 (s,1H), 4.18 (m, 1H), 3.72 (m, 2H), 3.38 (m, 4H), 2.98 (m, 3H), 2.63 (m,1H).

Example 1.9.2. (S)-3-((S)-6-fluoroisochroman-1-yl)morpholine (I-77) and(S)-3-((R)-6-fluoroisochroman-1-yl)morpholine (I-78)

(S)-3-((S)-6-fluoroisochroman-1-yl)morpholine (I-77) and(S)-3-((R)-6-fluoroisochroman-1-yl)morpholine (I-78) were prepared usinga procedure analogous to that described in Example 1.9.1, but using2-(3-fluorophenyl)ethanol in place of 2-phenylethanol.

(S)-3-((S)-6-fluoroisochroman-1-yl)morpholine (I-77): MS (ESI) m/z 238(M+H)⁺, ¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.23 (m, 1H), 6.97 (m, 1H),6.90 (m, 1H), 4.79 (s, 1H), 4.17 (m, 1H), 3.76 (m, 1H), 3.64 (m, 1H),3.39 (m, 4H), 3.00 (m, 3H), 2.65 (m, 1H).

(S)-3-((R)-6-fluoroisochroman-1-yl)morpholine (I-78): MS (ESI) m/z 238(M+H), ¹H NMR HCl salt, (400 MHz, MeOD) δ 7.23 (m, 1H), 6.97 (m, 1H),6.90 (m, 1H), 4.69 (s, 1H), 4.17 (m, 1H), 3.91 (m, 1H), 3.70 (m, 3H),3.47 (m, 1H), 3.29 (m, 1H), 3.03 (m, 1H), 2.82 (m, 2H), 2.67 (m, 1H).

Example 1.10. Procedure J Example 1.10.1.(S)-1-((S)-pyrrolidin-2-yl)isochroman-8-carbonitrile (I-37) and(R)-1-((S)-pyrrolidin-2-yl)isochroman-8-carbonitrile (I-38)

(a). (2S)-(9H-fluoren-9-yl)methyl2-(5-bromo-8-hydroxylisochroman-1-yl)pyrrolidine-1-carboxylate

4-bromo-3-(2-hydroxyethyl)phenol (4.0 g, 18.43 mmol),(S)-(9H-fluoren-9-yl)methyl 2-formylpyrrolidine-1-carboxylate (8.88 g,27.65 mmol) in toluene (40 mL) was stirred at 0° C.Trifluoromethanesulfonic acid (10 mL) was added dropwise to the solutionat this temperature. The mixture was stirred at 0° C. for an additional2-3 h and ice water (100 mL) was added. The mixture was filtered underreduced pressure, washed with methanol (100 mL). The filtrate wasconcentrated in vacuo and then extracted with ethyl acetate (3×100 mL).The combined organic layers were washed with brine (80 mL), dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo to affordthe crude product, which was purified by column chromatography(petroleum ether:ethyl acetate=20:1-10:1-5:1) to yield the desiredproduct as a colorless solid. MS (ESI) m/z 520.1 (M+H)⁺

(b). (S)-(9H-fluoren-9-yl)methyl2-((S)-8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate and(S)-(9H-fluoren-9-yl)methyl2-((R)-8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate

Palladium on activated carbon 10% Pd/C (3.2 g) was added to a solutionof (2S)-(9H-fluoren-9-yl)methyl2-(5-bromo-8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate (10.3 g,19.80 mmol) in methanol (150 mL). The mixture was stirred at roomtemperature under hydrogen overnight. The mixture was filtered through acelite pad under reduced pressure, washed with methanol (3×100 mL). Thecombined filtrate was concentrated in vacuum to afford the crudeproduct, which was purified by column chromatography (petroleumether:ethyl acetate=20:1-10:1-5:1) to afford the two stereoisomers,(S)-(9H-fluoren-9-yl)methyl2-((S)-8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxyl-ate (1.1 g) and(S)-(9H-fluoren-9-yl)methyl2-((R)-8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxyl-ate (2.1 g) aswhite solid. MS (ESI) m/z 442.1 (M+H) (c). (S)-(9H-fluoren-9-yl)methyl2-((S)-8-(trifluoromethylsulfonyloxy)isochroman-1-yl)pyrrolidine-1-carboxylate

Trifluoromethanesulfonic anhydride (1.35 mL, 2.26 mmol) was added to asolution of (2S)-(9H-fluoren-9-yl)methyl2-(8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate (500 mg, 1.13mmol), pyridine (890 mg, 11.3 mmol) in dichloromethane (60 mL) at 0° C.The mixture was stirred at 0° C. for about 2˜3 h and ice water (80 mL)was added. The mixture was extracted with dichloromethane (3×100 mL).The organic layers were combined, washed, dried, filtered, andconcentrated in vacuo to afford the crude product (850 mg) as a lightyellow oil, which was used in the next step without furtherpurification. MS (ESI) m/z 573.9 (M+H)⁺.

(d). (S)-1-((S)-pyrrolidin-2-yl)isochroman-8-carbonitrile (I-37)

A mixture of (S)-(9H-fluoren-9-yl)methyl2-((S)-8-(trifluoromethylsulfonyloxy)isochroman-1-yl)pyrrolidine-1-carboxylate (850 mg, 1.48 mmol),dicyanozinc (350 mg, 2.96 mmol), tetrakis(triphenylphosphine)platinum(350 mg, 0.30 mmol) in dimethyl sulfoxide (6 mL) was stirred at 120° C.under microwave reactor for 6.5 h. The mixture was filtered through acelite pad, washed with methanol (100 mL). The filtrate was concentratedand water (10 mL) was added. The mixture was extracted withdichloromethane:methanol=20:1 (3×80 mL). The organic layers werecombined, washed with brine (80 mL), dried, filtered, and concentratedin vacuo to afford the crude product, which was purified by Pre-HPLC toafford 1-37 (158 mg) as a light yellow oil. MS (ESI) m/z 228.9 (M+H)⁺.¹H NMR (HCl salt, 400 MHz, MeOD): δ 7.81 (d, J=7.6 Hz, 1H), 7.60˜7.49(m, 2H), 4.69 (d, J=11.6 Hz, 1H), 4.37˜4.32 (q, J=6.4 Hz, 1H), 3.97˜3.89(m, 1H), 3.85˜3.78 (m, 2H), 3.74˜3.66 (m, 1H), 3.19˜3.10 (m, 1H),2.86˜2.82 (dd, J¹=3.2 Hz, J²=13.6 Hz, 1H), 2.57˜2.52 (m, 1H), 2.38˜2.31(m, 1H), 2.14˜1.98 (m, 2H).

(e). (S)-(9H-fluoren-9-yl)methyl 2-((R)-8-(trifluoromethylsulfonyloxy)isochroman-1-yl)pyrrolidine-1-carboxylate

Trifluoromethanesulfonic anhydride (0.33 mL, 2 mmol) was added to asolution of (2S)-(9H-fluoren-9-yl)methyl2-((R)-8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate (441 mg, 1mmol), pyridine (790 mg, 10.0 mmol) in dichloromethane (60 mL) at 0° C.The mixture was stirred at 0° C. for about 2˜3 h and ice water (60 mL)was added. The mixture was extracted with dichloromethane (3×80 mL). Thecombined organic layers were washed with brine, dried, filtered, andconcentrated in vacuo to afford the crude product (713 mg) as a lightyellow oil, which was used in the next step without furtherpurification. MS (ESI) m/z 573.9 (M+H)⁺.

(f). (S)-1-((R)-pyrrolidin-2-yl)isochroman-8-carbonitrile (I-38)

A mixture of (S)-(9H-fluoren-9-yl)methyl2-((R)-8-(trifluoromethylsulfonyloxy)isochroman-1-yl)pyrrolidine-1-carboxylate (713 mg, 1.24 mmol),dicyanozinc (291 mg, 2.48 mmol), tetrakis(triphenylphosphine)platinum(1.43 g, 1.24 mmol) in dimethyl sulfoxide (6 mL) was stirred at 120° C.under microwave reactor for 6.5 h. The mixture was filtered through acelite pad, washed with methanol (100 mL). The filtrate was concentratedand water (10 mL) was added. The mixture was extracted withdichloromethane:methanol=20:1 (3×80 mL). The combined organic layerswere washed with brine (80 mL), dried, filtered, and concentrated invacuo to afford the crude product, which was purified by Pre-HPLC,followed by chiral HPLC purification using column: OZ-H 250*4.6 mm 5 μm;solvent: MeOH (0.1% DEA) to afford(S)-1-((R)-pyrrolidin-2-yl)isochroman-8-carbonitrile (I-38) as a lightyellow oil (86 mg). MS (ESI) m/z 228.9 (M+H)⁺. ¹H NMR (HCl, 400 MHz,MeOD): δ 8.03 (d, J=8.4 Hz, 1H), 7.71˜7.60 (m, 2H), 4.93 (d, J=8.4 Hz,1H), 4.32˜4.24 (m, 2H), 3.88˜3.83 (m, 1H), 3.72˜3.67 (m, 1H), 3.62˜3.56(m, 1H), 3.28˜3.20 (m, 1H), 3.09˜3.03 (m, 1H), 2.30˜2.12 (m, 4H).

Example 1.11. Procedure K Example 1.11.1.(S)-4,4-difluoro-2-((S)-isochroman-1-yl)pyrrolidine (I-63) and(S)-4,4-difluoro-2-((R)-isochroman-1-yl)pyrrolidine (I-64)

To a solution of (S)-tert-butyl4,4-difluoro-2-formylpyrrolidine-1-carboxylate (800 mg, 3.4 mmol)) wasadded 2-phenylethanol (0.42 g, 3.4 mmol) and trimethylsilyltrifluoromethanesulfonate (2.27 g, 10.2 mmol). The reaction mixture wasstirred at room temperature for 12 h. Water (100 mL) was added to thereaction vessel, and the resulting biphasic mixture was transferred to aseparatory funnel. The layers were separated, and the aqueous phase wasextracted with DCM (2×100 mL). The combined organics were dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo to afford thecrude product, which was purified by PREP-HPLC to afford(S)-4,4-difluoro-2-((S)-isochroman-1-yl)pyrrolidine (I-63, 200 mg) and(S)-4,4-difluoro-2-((R)-isochroman-1-yl)pyrrolidine (I-64, 180 mg).

(S)-4,4-difluoro-2-((S)-isochroman-1-yl)pyrrolidine (I-63): ESI: m/z=240(M+H⁺). ¹HNMR (400 MHz, CDCl₃): δ 7.25-7.18 (m, 2H), 7.17-7.10 (m, 2H),5.01 (s, 1H), 4.25 (ddd, J=11.1, 5.8, 1.3 Hz, 1H), 3.97-3.86 (m, 1H),3.81-3.74 (m, 1H), 3.46-3.38 (m, 1H), 3.22-3.00 (m, 2H), 2.64 (d, J=16.2Hz, 1H), 2.21-2.01 (m, 2H), 1.96-1.84 (m, 1H).

(S)-4,4-difluoro-2-((R)-isochroman-1-yl)pyrrolidine (I-64): ESI: m/z=240(M+H⁺). ¹HNMR (400 MHz, CDCl₃): δ 7.25-7.18 (m, 2H), 7.17-7.10 (m, 2H),5.01 (s, 1H), 4.25 (ddd, J=11.1, 5.8, 1.3 Hz, 1H), 3.97-3.86 (m, 1H),3.81-3.74 (m, 1H), 3.46-3.38 (m, 1H), 3.22-3.00 (m, 2H), 2.64 (d, J=16.2Hz, 1H), 2.21-2.01 (m, 2H), 1.96-1.84 (m, 1H).

Example 1.12. Procedure L. Certain Provided Compounds were MadeFollowing a Procedure Exemplified by Example 1.12.1 Example 1.12.1.(S)-2-((R)-6-fluoroisochroman-1-yl)-1-methylpyrrolidine (I-69)

To a solution of (S)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-9,0.13 g, 0.6 mmol) in methanol (10 mL) was added (HCHO)n (0.09 g, 3 mmol)and NaCNBH₃ (0.15 g, 2.4 mmol) at room temperature. The mixture wasstirred at this temperature overnight. The mixture was concentrated invacuo to give the residue, which was purified by prep-HPLC, followed byneutralization with NaHCO₃ (aq. sat.). The solution was extraction withDCM (50 mL×2). The organic layers were dried, filtered, and solventevaporated in vacuo to give the desired product as yellow oil (80 mg).(ESI) m/z: 236[M+H]⁺. ¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.27˜7.23 (dd,J¹=5.6 Hz, J²=8.8 Hz, 1H), 7.04˜6.98 (m, 2H), 5.33 (s, 1H), 4.34˜4.30(m, 1H), 4.18˜4.13 (m, 1H), 3.87˜3.80 (m, 1H), 3.73˜3.67 (m, 1H),3.28˜3.21 (q, J=8.8 Hz, 1H), 3.16˜3.10 (m, 4H), 2.75˜2.71 (d, J=16.4Hz), 2.11˜1.67 (m, 4H).

Example 1.12.2. (S)-1-ethyl-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine(I-70)

(S)-1-ethyl-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-70) wasprepared using a procedure analogous to that described in Example1.12.1, but using acetaldehyde in place of (HCHO)n. ESI) m/z: 250[M+H]⁺.¹H NMR (HCl salt, 400 MHz, MeOD) δ 7.27˜7.24 (dd, J¹=5.6 Hz, J²=8.4 Hz,1H), 7.05˜6.98 (m, 2H), 5.31 (s, 1H), 4.37˜4.30 (m, 1H), 4.23˜4.18 (m,1H), 3.86˜3.59 (m, 3H), 3.30˜3.08 (m, 3H), 2.75˜2.71 (d, J=16.4 Hz, 1H),2.08˜1.94 (m, 2H), 1.87˜1.75 (m, 2H), 1.49˜1.43 (t, 3H).

Example 1.13. Procedure M. Certain Provided Compounds were MadeFollowing a Procedure Exemplified by Example 1.13.1 Example 1.13.1.(S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-118)and (S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine(I-119)

(a). (2-bromo-5-fluorobenzyloxy)(tert-butyl)dimethylsilane

To a solution of (2-bromo-5-fluorophenyl)methanol (25.6 g, 124.86 mmol)in dichloromethane (750 mL) was added 1H-imidazole (17 g, 249.72 mmol)and tert-butylchlorodimethylsilane (37.64 g, 249.72 mmol). The reactionmixture was stirred at room temperature for 16 h and was then washedwith brine (3×200 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (eluted with petroleum ether) to give the productas a colorless oil (36.2 g).

(b).(2S)-tert-butyl2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate

To a solution of ((2-bromo-5-fluorobenzyl)oxy)(tert-butyl)dimethylsilane(3.19 g, 10 mmol) in toluene (25 mL) was added dropwisetert-butyllithium (0.96 g, 15 mmol) at −78° C. The reaction was stirredat 0° C. for 1 h. (S)-tert-Butyl 2-formylpyrrolidine-1-carboxylate (2.99g, 15 mmol)) in toluene (10 mL) was added dropwise. The reaction mixturewas stirred at −78° C. for 3 h and poured into iced-water. The organicphase was separated and washed with brine (3×70 mL), dried over sodiumsulfate and evaporated in vacuo to give the crude, which was purified bycolumn chromatography (PE:EtOAc=15:1) to give the tittle compound (4 g)as colorless oil.

(c).(S)-tert-butyl2-((4-fluoro-2-(hydroxymethyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate

To a solution of (2S)-tert-butyl2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate(5.5 g, 11.4 mmol) in tetrahydrofuran (100 mL) was addedtetrabutylammonium fluoride (2.98 g, 11.4 mmol). The reaction mixturewas stirred at ambient temperature for 16 h and then concentrated togive a residue, which was diluted with ethyl acetate (200 mL),neutralized with saturated sodium bicarbonate solution, washed withbrine (4×50 mL), dried over sodium sulfate and concentrated in vaccuo.The crude product was purified by silica gel column chromatography(eluted with petroleum ether:ethyl acetate=5:1) to give the titlecompound as a colorless oil (3.3 g), MS (ESI): m/z 326 [M+H]⁺.

(d). (S)-tert-butyl2-((4-fluoro-2-((methylsulfonyloxy)methyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate

To a solution of (2S)-tert-butyl2-((4-fluoro-2-(hydroxymethyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (3 g, 7.38 mmol) in ethyl acetate (150mL) was added methanesulfonyl chloride (0.8 g, 7.01 mmol). The reactionmixture was stirred at room temperature for 30 min and then washed withwater (3×100 mL). The organic layer was dried over sodium sulfate,filtered and concentrated to give the crude product (3.4 g), which wasused in the next step without further purification.

(e). (S)-tert-butyl2-(5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine-1-carboxylate

To a solution of (2S)-tert-butyl2-((4-fluoro-2-(((methylsulfonyl)oxy)methyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (3 g, 7.44 mmol) intetrahydrofuran (150 mL) was added potassium 2-methylpropan-2-olate (2.5g, 22.32 mmol). The reaction mixture was stirred at room temperature for1 h. Upon completion, water (100 mL) and ethyl acetate (100 mL) wereadded to the mixture. The organic layer was separated, washed with water(3×80 mL), dried over sodium sulfate, filtered and then concentrated togive the residue. The residue was purified by silica gel columnchromatography (eluted with petroleum ether:ethyl acetate=20:1) to givethe title compound (1.9 g) as colorless oil.

(f). (S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine(I-118) and(S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-119)

To a solution of (2S)-tert-butyl2-(5-fluoro-1,3-dihydroisobenzofuran-1-yl) pyrrolidine-1-carboxylate(100 mg, 0.33 mmol) in methanol (10 mL) was added HCl/1,4-dioxane (0.58g, 16 mmol). The reaction mixture was stirred at room temperature for 1h to yield the a mixture of two diastereoisomers, which was separated byHPLC to give(S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-118)and (S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine(I-119).

(S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-118):ESI: m/z=208 (M+H)⁺. ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.39-7.43 (m,1H), 7.11-7.14 (m, 2H), 5.38 (s, 1H), 5.08-5.26 (m, 2H), 3.90-3.95 (m,1H), 3.29-3.33 (m, 1H), 2.01-2.33 (m, 6H).

(S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-119):ESI: m/z=208 (M+H)⁺. ¹HNMR (HCl salt, 400 MHz, MeOD): δ 7.35-7.38 (m,1H), 7.10-7.14 (m, 2H), 5.63 (s, 1H), 5.15-5.26 (m, 2H), 4.12-4.16 (m,1H), 3.34-3.38 (m, 1H), 1.95-2.12 (m, 2H), 1.62-1.79 (m, 4H).

Example 1.13.2.(R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-120)and (R)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (121)

(R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-120)and (R)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine(I-121) were prepared using a procedure analogous to that described inExample 1.13.1, but using (R)-tert-butyl2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate.

(R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-120):ESI: m/z=208 (M+H)⁺. ¹HNMR (400 MHz, MeOD): δ 7.36-7.40 (m, 1H),7.11-7.13 (m, 2H), 5.63 (s, 1H), 5.15-5.25 (m, 2H), 4.14-4.18 (m, 1H),3.33-3.38 (m, 1H), 1.95-2.10 (m, 2H), 1.62-1.81 (m, 4H).

(R)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-121):ESI: m/z=208 (M+H)⁺. ¹HNMR (400 MHz, MeOD): δ 7.40-7.43 (m, 1H),7.10-7.14 (m, 2H), 5.39 (s, 1H), 5.08-5.37 (m, 2H), 3.90-3.96 (m, 1H),3.28-3.33 (m, 1H), 2.08-2.35 (m, 6H).

Example 1.14. Procedure N. Certain Provided Compounds were MadeFollowing a Procedure Exemplified by Example 1.14.1 Example 1.14.1.(S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-126)and (S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine(I-133)

(a). 2-((2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran

To a solution of (2-bromo-5-fluorophenyl)methanol (40 g, 195 mmol) indichloromethane (200 ml) at 0° C. was added 4-methylbenzenesulfonic acid(1 g, 5.85 mmol) and 3,4-dihydro-2H-pyran (24.5 g, 292 mmol). Themixture was stirred at room temperature for 6 h. Saturated aqueousNaHCO₃ (300 mL) was added to the reaction vessel, and the resultingbiphasic mixture was transferred to a separatory funnel. The layers wereseparated, and the organic phase was washed with saturated aqueous NaCl(2×100 mL). The combined organics were dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The resulting oil waspurified by flash column chromatography with an isocratic elution ofEtOAc (5%) and petroleum ether (95%) to provide2-((2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran (41.9 g, 145 mmol) asa colorless oil.

(b). (2S)-tert-butyl-2-(4-fluoro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)benzoyl)azetidine-1-carboxylate

To a solution of 2-((2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran(11.5 g, 40 mmol) in THF (40 ml) was added magnesium (1.94 g, 80 mmol)and a grain of iodine. The mixture was stirred at reflux for 2 h. Uponcompletion,(S)-tert-butyl-2-(methoxy-(methyl)carbamoyl)azetidine-1-carboxylate(4.88 g, 20 mmol) was added at 0° C. The reaction mixture was stirred atthis temperature for 3 h. Water (100 mL) was added to the reactionvessel, and the resulting biphasic mixture was transferred to aseparatory funnel. The organic layer was separated and the aqueous layerwas extraction with EtOAc (2×100 mL). The combined organics were driedover anhydrous sodium sulfate, filtered and concentrated in vacuo toafford the crude product, which was purified by flash columnchromatography with an isocratic elution of EtOAc (20%) and petroleumether (80%) to afford the title compound (6 g) as a colorless oil.

(c).(2S)-tert-butyl-2-((4-fluoro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-(hydroxy)methyl)azetidine-1-carboxylate

To a solution of (2S)-tert-butyl2-(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl) oxy)methyl)benzoyl)azetidine-1-carboxylate (6 g, 15.2 mmol) in MeOH (30 ml) wasadded NaBH₄ (0.575 g, 15.2 mmol). The mixture was stirred at roomtemperature for 3 h. Water (100 mL) was added to the reaction vessel,and the resulting biphasic mixture was transferred to a separatoryfunnel and extracted with EtOAc (2×200 mL). The combined organics weredried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The resulting oil was purified by reverse phase HPLC to provide thetitle compound (5.2 g) as a white solid.

(d). (2S)-tert-butyl 2-((4-fluoro-2-(hydroxymethyl)phenyl) (hydroxy)methyl)azetidine-1-carboxylate

To a solution of (2S)-tert-butyl2-((4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)(hydroxy)methyl)azetidine-1-carboxylate (3 g, 7.58 mmol) in MeOH(50 ml) was added 4-methylbenzenesulfonic acid (130 mg, 0.758 mmol). Themixture was stirred at room temperature for 3 h. Saturated aqueousNaHCO₃ (60 mL) was added to the reaction vessel, and the resultingbiphasic mixture was transferred to a separatory funnel and extractedwith DCM (2×50 mL). The combined organics were dried over anhydroussodium sulfate, filtered and concentrated in vacuo. Crude product wasused in next step without further purification.

(e). (2S)-tert-butyl2-(5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine-1-carboxylate

To a solution of ((2S)-tert-butyl2-((4-fluoro-2-(hydroxymethyl)phenyl)(hydroxy)methyl)azetidine-1-carboxylate (8 g, 25.7 mmol) in DCM (30 ml) was addedMsCl (5 g, 30.1 mmol), Et₃N (0.35 g, 2.57 mmol). The mixture was stirredat room temperature for 3 h. Solvent was removed and to the residuet-BuOK (3.37 g, 30.1 mmol) in THF (30 mL) was added. The mixture wasstirred at room temperature for 5 h and then transferred to a separatoryfunnel and extracted with DCM (2×200 mL). The combined organics weredried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The resulting oil was purified by flash column chromatography with anisocratic elution of EtOAc (10%) and petroleum ether (90%) to providethe title compound (5.6 g) as a white solid. ESI: m/z=605 (M+1)

(f). ((S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine(I-126) and (S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine(I-133)

To a solution of (2S)-tert-butyl2-(5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine-1-carboxylate (5.6g, 19.3 mmol) in DCM (30 ml) was added TFA (2.1 g, 21.2 mmol). Themixture was stirred at 0° C. for 3 h. Water (50 mL) was added to thereaction vessel, and the mixture was adjusted to pH=9 with solid NaHCO₃.The resulting biphasic mixture was transferred to a separatory funneland extracted with DCM (3×100 mL). The combined organics were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to givecrude, which was purified by PREP-HPLC to give((S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-126)(200 mg) and (S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine(I-133) as oil. ESI: m/z=194 (M+H⁺).

((S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-126): ¹HNMR (400 MHz, MeOD) δ 7.21 (dd, J=8.3, 4.8 Hz, 1H), 7.07-6.89 (m, 2H),5.29 (s, 1H), 5.16 (dd, J=12.7, 2.1 Hz, 1H), 5.01 (d, J=12.8 Hz, 1H),4.75-4.72 (m, 1H), 3.94-3.91 (m, 1H), 3.75-3.68 (m, 1H), 2.51-2.43 (m,1H), 2.58-2.40 (m, 1H).

Example 1.14.2.(R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-127) and(R)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-128)

(R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-127) and(R)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-128) wereprepared using a procedure analogous to that described in Example1.14.1, but using (R)-tert-butyl2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate in place of(S)-tert-butyl 2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate.

(R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-127):ESI: m/z=194 (M+H⁺). ¹H NMR (400 MHz, MeOD) δ 7.25 (dd, J=8.3, 4.8 Hz,1H), 7.09-6.96 (m, 2H), 5.33 (s, 1H), 5.20 (dd, J=12.7, 1.9 Hz, 1H),5.03 (dd, J=12.7, 1.1 Hz, 1H), 4.90-4.81 (m, 1H), 4.01 (dd, J=18.9, 9.3Hz, 1H), 3.78 (td, J=10.1, 5.5 Hz, 1H), 3.23 (dt, J=3.3, 1.6 Hz, 1H),2.77 (ddt, J=11.9, 9.9, 8.6 Hz, 1H), 2.59-2.47 (m, 1H), 1.92-1.91 (m,1H).

(R)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-128):ESI: m/z=194 (M+H⁺). ¹H NMR (400 MHz, MeOD) δ 7.25 (dd, J=8.3, 4.8 Hz,1H), 7.09-6.96 (m, 2H), 5.33 (s, 1H), 5.20 (dd, J=12.7, 1.9 Hz, 1H),5.03 (dd, J=12.7, 1.1 Hz, 1H), 6.84-4.36 (m, 8H), 4.90-4.81 (m, 1H),4.01 (dd, J=18.9, 9.3 Hz, 1H), 5.34-2.59 (m, 1H), 3.78 (td, J=10.1, 5.5Hz, 1H), 3.23 (dt, J=3.3, 1.6 Hz, 1H), 2.77 (ddt, J=11.9, 9.9, 8.6 Hz,1H), 2.59-2.47 (m, 1H), 1.92-1.91 (m, 1H), 1.08-0.90 (m, 1H).

Example 1.15. Procedure O. Certain Provided Compounds were MadeFollowing a Procedure Exemplified by Example 1.15.1 Example 1.15.1.(R)-2-((S)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine(I-125)

(a). 2-(2-bromo-5-fluorobenzyloxy)tetrahydro-2H-pyran

To a solution of (2-bromo-5-fluorophenyl)methanol (20 g, 97.5 mmol) inCH₂Cl₂ (100 ml) was added 4-methylbenzenesulfonic acid (0.502 g, 2.92mmol) and 3,4-dihydro-2H-pyran (12.2 g, 146 mmol) at 0° C. The reactionwas stirred at ambient temperature for 2 h. Upon completion, saturatedaqueous NaHCO₃ (100 mL) was added to the reaction vessel, and theresulting biphasic mixture was transferred to a separatory funnel. Thelayers were separated, and the organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The resulting oil waspurified by flash column chromatography with an isocratic elution ofpetroleum ether (100%) and EtOAc (5%) to provide the title compound(22.9 g) as a colorless oil.

(b). (2R)-tert-butyl2-(1-(4-fluoro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate

To a solution of 2-((2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran(8.67 g, 30 mmol) in THF (40 ml) was added magnesium (1.45 g, 60 mmol)and one grain of iodine. The reaction was stirred at reflux for 2 h.Upon completion, (R)-tert-butyl 2-acetylpyrrolidine-1-carboxylate (6.12g, 28.7 mmol) was added at 0° C. The mixture was stirred at thistemperature for 3 h. Upon completion, water (50 mL) was added to thereaction vessel, and the resulting biphasic mixture was transferred to aseparatory funnel and extracted with EtOAc (2×50 mL). The combinedorganics were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to afford an oil, which was purified by flash columnchromatography with an isocratic elution of EtOAc (10%) and petroleumether (90%) to provide the title compound (3.49 g) as a colorless oil.

(c). (2R)-tert-butyl2-(1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate

To a solution of (2R)-tert-butyl2-(1-(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (4 g, 9.44 mmol)in MeOH (100 mL) was added 4-methylbenzenesulfonic acid (323 mg, 1.88mmol). The mixture was stirred at ambient temperature for 6 h. Uponcompletion, the solvent was evaporated in vacuo to afford an oil. Water(100 mL) was added to the reaction vessel, and the resulting biphasicmixture was transferred to a separatory funnel and extracted with DCM(2×100 mL). The combined organics were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to afford a white solid, which wasused in the next step without further purification. ESI: m/z=340 (M+H⁺).

(d). (R)-2-((S)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-125)

To a solution of (2R)-tert-butyl2-(1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate(1.2 g, 3.53 mmol) in CH₂Cl₂ (10 ml) was added trimethylsilyltrifluoromethanesulfonate (2.33 g, 10.5 mmol). The mixture was stirredat ambient temperature for 3 h. Water (60 mL) was added to the reactionvessel, and the resulting biphasic mixture was transferred to aseparatory funnel and extracted with DCM (2×60 mL). The combinedorganics were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The resulting oil was purified by reverse phase HPLC to provide1-125 (497 mg). ESI: m/z=222 (M+H⁺). ¹H NMR (400 MHz, MeOD) δ 7.46-7.37(m, 1H), 7.20-7.07 (m, 2H), 5.22 (d, J=13.0 Hz, 1H), 5.11 (d, J=13.0 Hz,1H), 4.14 (dd, J=12.1, 4.7 Hz, 1H), 3.28 (t, J=6.9 Hz, 2H), 2.43-2.27(m, 1H), 2.24-2.01 (m, 3H), 1.51 (s, 3H).

Example 1.15.2.(S)-2-((R)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine(I-122)

(S)-2-((R)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine(I-122) was prepared using a procedure analogous to that described inExample 1.15.1, but using (S)-tert-butyl2-acetylpyrrolidine-1-carboxylate in place of (R)-tert-butyl2-acetylpyrrolidine-1-carboxylate. ESI: m/z=222 (M+H⁺). ¹H NMR (400 MHz,MeOD) δ 7.32 (dd, J=8.3, 4.8 Hz, 1H), 7.18-7.02 (m, 2H), 5.26-5.07 (m,2H), 4.09-3.96 (m, 1H), 3.40-3.33 (m, 2H), 2.09-1.91 (m, 2H), 1.71-1.67m, 1H), 1.65-1.52 (m, 4H).

Example 1.16. Procedure P. Certain Provided Compounds were MadeFollowing a Procedure Exemplified by Example 1.16.1 Example 1.16.1.((R)-2-((R)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine(I-124)

(a). (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic anhydride

To a solution of (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylicacid (20 g, 92.9 mmol) in CH₂Cl₂ (100 ml) was addedN,N′-methanediylidenedicyclohexanamine (9.57 g, 46.4 mmol). The reactionwas stirred at room temperature for 24 h. Upon completion, the whitesolid was filtered off. The filtrate was evaporated in vacuo to give anoil. After addition of ether (100 mL), the solid precipitation wasfiltered off. The filtrate was evaporated in vacuo to give the crudeproduct, which was used in next step without further purification.

(b). (2R)-tert-butyl 2-(4-fluoro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)benzoyl)-pyrrolidine-1-carboxylate

To a solution of 2-((2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran (7g, 24.2 mmol) in THF (20 ml) was added magnesium (1.17 g, 48.4 mmol).The mixture was stirred at reflux for 2 h. Upon completion,(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)magnesiumbromide (7.58 g, 24.2 mmol) was added. The reaction was stirred at thistemperature for 3 h. Upon completion, water (50 mL) was added to thereaction vessel, and the resulting biphasic mixture was transferred to aseparatory funnel and extracted with EtOAc (2×50 mL). The combinedorganics were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The resulting oil was purified by flash column chromatographywith an isocratic elution of EtOAc (10%) and petroleum ether (90%) toprovide the title compound (5 g) as a colorless oil.

(c). (2R)-tert-butyl2-(1-(4-fluoro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate

To a solution of (2R)-tert-butyl2-(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)benzoyl)pyrrolidine-1-carboxylate (2.0 g, 4.90 mmol) in THF (20 ml) wasadded methylmagnesium bromide (4.89 mL, 14.7 mmol). The mixture wasstirred at ambient temperature for 3 h. Saturated aqueous NH₄Cl (100 mL)was added to the reaction vessel, and the resulting biphasic mixture wastransferred to a separatory funnel, and extracted with EtOAc (2×100 mL).The combined organics were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the crude product, which was used in nextstep without further purification. ESI: m/z=446 (M+Na⁺).

(d). Preparation of (2R)-tert-butyl2-(1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxyl-ethyl)pyrrolidine-1-carboxylate

To a solution of (2R)-tert-butyl2-(1-(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (2.1 g, 4.95mmol) in MeOH (80 ml) was added 4-methylbenzenesulfonic acid (85.2 mg,495 μmol). The mixture was stirred at room temperature for 3 h, and thensolvent evaporated in vacuo to give an oil. Saturated aqueous NaHCO₃ (10mL) was then added to the reaction vessel, and the resulting biphasicmixture was transferred to a separatory funnel and extracted with EtOAc(2×100 mL). The combined organics were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The resulting oil was purified byflash column chromatography with an isocratic elution of EtOAc (20%) andpetroleum ether (80%) to provide the title compound (1.49 g) as acolorless oil. ESI: m/z=340 (M+H⁺).

(e). (R)-tert-butyl2-((S)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine-1-carboxylate

To a solution of (2R)-tert-butyl2-(1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (1.6 g, 4.71 mmol) in CH₂Cl₂ (30 ml) at0° C. was added triethylamine (2.37 g, 23.5 mmol) and then followed bymethanesulfonyl chloride (1.61 g, 14.1 mmol). The mixture was stirred atambient temperature for 3 h. Water (100 mL) was added to the reactionvessel, and the resulting biphasic mixture was transferred to aseparatory funnel. The layers were separated, and the organic phase waswashed with saturated aqueous NaCl (2×50 mL). The combined organics weredried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresulting oil was purified by flash column chromatography with anisocratic elution of EtOAc (10%) and petroleum ether (90%) to providethe title compound (1.09 g) as a white solid.

(f). (R)-2-((R)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-124)

To a solution of (2R)-tert-butyl2-(5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine-1-carboxylate(500 mg, 1.55 mmol) in CH₂Cl₂ (10 ml) was added 2,2,2-trifluoroaceticacid (1.76 g, 15.5 mmol). The reaction was stirred at room temperaturefor 2 h. Upon completion, the reaction mixture was evaporated in vacuoto afford the crude product. The resulting oil was purified by reversephase HPLC to provide 1-124 (200 mg) as a colorless oil. ESI: m/z=222(M+1). ¹H NMR (500 MHz, MeOD): δ 7.25 (dd, J=8.3, 4.8 Hz, 1H), 7.05 (dd,J=15.0, 8.6 Hz, 2H), 5.18-5.03 (m, 2H), 3.58-3.41 (m, 1H), 3.14-3.09 (m,1H), 2.96-2.91 (m, 1H), 1.83-1.74 (m, 2H), 1.62-1.49 (m, 4H), 1.45-1.37(1H).

Example 1.16.2.(S)-2-((S)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine(I-123)

(S)-2-((S)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine(I-123) was prepared using a procedure analogous to that described inExample 1.16.1, but using(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid in place of(R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid. ESI: m/z=222(M+H⁺). ¹H NMR (400 MHz, MeOD) δ 7.22 (dd, J=8.2, 4.9 Hz, 1H), 7.11-6.90(m, 2H), 5.19-5.00 (m, 2H), 3.13-2.94 (m, 1H), 2.81-2.77 (m, 1H),1.83-1.64 (m, 2H), 1.53 (s, 3H), 1.49-1.41 (m, 1H), 1.39-1.29 (m, 1H).

Example 1.17. Procedure Q Example 1.17.1.2-((S)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)pyridine (I-57) and2-((R)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)pyridine (I-58)

(a). (S)-2-((S)-6-bromoisochroman-1-yl)pyrrolidine and(S)-2-((R)-6-bromoisochroman-1-yl)pyrrolidine

To a solution of 2-(3-bromophenyl)-ethanol (10 g, 49.7 mmol) in DCM (100mL) was added (S)-pyrrolidine-2-carbaldehyde (5.9 g, 59.6 mmol) at 0° C.Trifluoromethanesulfonic acid (37.2 g, 248 mmol) was added dropwise.After addition, the mixture was stirred at this temperature for 8 h.Upon completion, water (5 mL) was added to the reaction vessel and theresulting biphasic mixture was transferred to a separatory funnel. Thelayers were separated and the aqueous phase was extracted with EtOAc(2×50 mL). The combined organics were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give a mixture of twodiastereoisomers, which was separated by Chiral-HPLC (Column: OZ-H250*4.6 mm 5 μm, Moblie Phase: MeOH (0.1% DEA) to yield(S)-2-((S)-6-bromoisochroman-1-yl)pyrrolidine (6.12 g) and(S)-2-((R)-6-bromoisochroman-1-yl)pyrrolidine (6.13 g). MS (ESI) m/z 284[M+H]⁺.

(b). (S)-tert-butyl2-((S)-6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate

To a solution of (S)-2-((S)-6-bromoisochroman-1-yl)pyrrolidine (6 g,21.2 mmol) in NaOH/Water (30 ml) at room temperature was addedditertbutyl dicarbonate (5.54 g, 25.4 mmol). The reaction was stirred atthis temperature for 2 h. Upon completion, the resulting biphasicmixture was transferred to a separatory funnel. The layers wereseparated and the aqueous phase was washed with DCM (2×50 mL). Thecombined organics were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. MS (ESI) m/z: 384 [M+H]⁺.

(c). (S)-tert-butyl 2-((S)-6-(pyridin-2-yl)isochroman-1-yl)pyrrolidine-1-carboxylate

To a solution of (S)-tert-butyl2-((S)-6-bromoisochroman-1-yl)pyrrolidine-1-car boxylate (2 g, 5.23mmol) in toluene (50 ml) was added 2-(tributylstannyl)pyridine (2.3 g,6.27 mmol) and palladium-triphenylphosphane (1:4) (6.04 mg, 0.523 mmol).The mixture was stirred at 110° C. for 6 h. Upon completion, water (5mL) was added to the reaction vessel and the resulting biphasic mixturewas transferred to a separatory funnel. The layers were separated andthe aqueous phase was washed with EtOAc (2×50 mL). The combined organicswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The resulting oil was purified by flash column chromatography (petroleumether/EtOAc from 20:1 to 5:1) to provide the title product (1.36 g) as acolorless oil. MS (ESI) m/z: 381 [M+H]⁺.

(d). 2-((S)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)pyridine (I-57)

To a solution of (S)-tert-butyl2-((S)-6-(pyridin-2-yl)isochroman-1-yl)pyrrolidine-1-carboxylate (500mg, 1.31 mmol) in dichloromethane (50 mL), trifluoroacetic acid (224 mg,1.97 mmol) was added dropwise at 0° C. After addition, the mixture wasstirred at this temperature for about 3 h. After workup,2-((S)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)pyridine (I-57) wasobtained. MS (ESI) m/z: 281 [M+H]⁺. ¹H NMR (HCl salt, 400 MHz, MeOD): δ8.89 (d, J=5.8 Hz, 1H), 8.78-8.68 (m, 1H), 8.46 (d, J=8.2 Hz, 1H), 8.10(t, J=6.8 Hz, 1H), 7.97-7.86 (m, 2H), 7.70 (d, J=8.2 Hz, 1H), 5.17 (d,J=2.2 Hz, 1H), 4.91 (s, 11H), 4.45-4.33 (m, 2H), 3.92 (td, J=11.3, 3.3Hz, 1H), 3.66-3.14 (m, 6H), 2.92 (d, J=16.6 Hz, 1H), 2.35 (dt, J=16.8,6.9 Hz, 2H), 2.15 (ddd, J=21.1, 13.0, 6.0 Hz, 2H).

(e). 2-((R)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)pyridine (I-58)

1-58 was synthesized using the same method as Compound 1-57 as describedabove. (ESI) m/z: 281 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.72-8.65 (m,1H), 7.82-7.68 (m, 3H), 7.31-7.19 (m, 3H), 5.04 (d, J=2.4 Hz, 1H), 4.23(ddd, J=11.1, 5.7, 1.6 Hz, 1H), 3.77 (td, J=11.3, 3.0 Hz, 1H), 3.69-3.60(m, 1H), 3.48 (s, 1H), 3.20-2.95 (m, 2H), 2.85 (dt, J=11.1, 7.6 Hz, 1H),2.73 (d, J=16.2 Hz, 1H), 2.01 (s, 4H), 1.70 (dd, J=14.3, 7.0 Hz, 2H),1.49 (ddd, J=15.0, 7.7, 2.7 Hz, 2H).

Example 1.18. Procedure R. Certain Provided Compounds were MadeFollowing a Procedure Exemplified by Example 1.18.1 Example 1.18.1.5-((S)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)isoxazole (I-55)

(a). (S)-tert-butyl2-((S)-6-acetylisochroman-1-yl)pyrrolidine-1-carboxylate

To a solution of (S)-tert-butyl2-((S)-6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate (1.5 g, 3.32mmol) in THF (25 mL) was added n-BuLi (1.6 N in hexane) (3.1 mL) at −78°C. under nitrogen. After the mixture was stirred at this temperature for1 h, a solution of N-methoxy-N-methylacetamide (444 mg, 4.31 mmol) inTHF (2 mL) was added. The mixture was allowed to warm to roomtemperature and stirred for another 1 h. The mixture was quenched withwater (100 mL), extracted with EtOAc (70 mL×2), dried and concentratedin vacuo to give the crude, which was purified by prep-TLC, eluted withPE:EtOAc=5:1 to yield the title compound.

(b). (S)-tert-butyl 2-((S)-6-((E)-3-(dimethylamino)acryloyl)isochroman-1-yl)pyrrolidine-1-carboxylate

A solution of (S)-tert-butyl2-((S)-6-acetylisochroman-1-yl)pyrrolidine-1-carboxylate (520 mg, 1.50mmol) and DMF-DMA (0.535 g, 4.5 mmol) was heated to 100° C. withstirring overnight. The mixture was concentrated in vacuo to give thecrude, which was used directly in the next step. (ESI) m/z: 401[M+H]⁺.

(c). (S)-tert-butyl 2-((S)-6-(isoxazol-5-yl)isochroman-1-yl)pyrrolidine-1-carboxylate

To a solution of (S)-tert-butyl 2-((S)-6-((E)-3-(dimethylamino)acryloyl)isochroman-1-yl)pyrrolidine-1-carboxylate (720 mg, 0.876 mmol) in MeOH(30 mL) was added hydroxylamine hydrochloride (182 mg, 2.62 mmol). Themixture was heated to 70° C. with stirring for 3 h. The mixture wasconcentrated in vacuo to give the crude, which was diluted with water(100 mL), extracted with DCM (70 mL×2). The organic phase was dried,filtered and concentrated in vacuo to give the crude product. (ESI) m/z:315[M-56+H]⁺.

(d). 5-((S)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)isoxazole (I-55)

To a solution of (S)-tert-butyl 2-((S)-6-(isoxazol-5-yl)isochroman-1-yl)pyrrolidine-1-carboxylate (420 mg, 0.812 mmol) in DCM (5 mL) was added3N HCl/dioxane (6 mL) at room temperature. The mixture was stirred atroom temperature for 3 h and then concentrated in vacuo to give thecrude, which was purified by prep. HPLC to give a residue. The residuewas freeze-dried to give the TFA salt, which was basified with sat.NaHCO₃, extracted with DCM/MeOH=20:1 (50 mL×2), dried and concentratedin vacuo to yield I-55. (ESI) m/z: 271[M+H]⁺. ¹HNMR(HCl salt, 400 MHz,MeOD): δ 8.46 (s, 1H), 7.81-7.79 (d, J=8.0 Hz, 1H), 7.75 (s, 1H),7.51-7.49 (d, J=8.0 Hz, 1H), 6.85 (s, 1H), 5.09 (s, 1H), 4.37-4.28 (m,2H), 3.91-3.85 (m, 1H), 3.30-3.23 (m, 3H), 2.84-2.80 (d, J=16.4 Hz, 1H),2.34-2.25 (m, 2H), 2.20-2.04 (m, 2H).

Example 1.18.2. 5-((R)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)isoxazole(I-56)

5-((R)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)isoxazole (I-56) wasprepared using a procedure analogous to that described in Example1.18.1, but using (S)-tert-butyl2-((R)-6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate in place of(S)-tert-butyl 2-((S)-6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate.(ESI) m/z: 271[M+H]⁺. ¹HNMR (400 MHz, MeOD): δ 8.46-8.45 (d, J=2.0 Hz,1H), 7.76-7.74 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.41-7.39 (d, J=7.6 Hz,1H), 6.84-6.83 (d, J=1.6 Hz, 1H), 5.28 (s, 1H), 4.46-4.41 (m, 1H),4.37-4.33 (m, 1H), 3.88-3.81 (m, 1H), 3.40-3.37 (m, 2H), 3.21-3.13 (m,1H), 2.83-2.79 (d, J=16.4 Hz, 1H), 2.09-1.95 (m, 2H), 1.83-1.77 (m, 2H).

Example 1.19. Procedure S Example 1.19.1.3-(6-fluoroisochroman-1-yl)pyrrolidine (I-129, I-130, I-131, I-132)

To a mixture of tert-butyl 3-formylpyrrolidine-1-carboxylate (550 mg,2.76 mmol) and 2-(3-fluorophenyl)ethanol (386 mg, 2.76 mmol) was addedtrifluoromethanesulfonic acid (1.24 g, 8.28 mmol) at 0° C. The mixturewas stirred at room temperature for another 2 h. Upon completion, themixture was quenched with sat. NaHCO₃ (100 mL) till pH>7, extracted withDCM (80 mL×2). The organic layers were dried and concentrated to givethe crude, which was purified by prep-HPLC to give the desired productas TFA salt, which was basified with sat. NaHCO₃ (30 mL) again,extracted with DCM (2×20 mL), dried and concentrated in vacuo to yieldthe mixture of 4 stereoisomers. (ESI) m/z: 222[M+H]⁺. ¹HNMR (400 MHz,CDCl₃): δ 7.11-7.06 (m, 1H), 6.92-6.87 (m, 1H), 6.84-6.82 (m, 1H),4.80-4.78 (d, J=6.8 Hz, 1H), 4.21-4.16 (m, 1H), 3.87 (s, 1H), 3.72-3.64(m, 1H), 3.25-2.76 (m, 6H), 2.63-2.58 (d, J=16.8 Hz, 1H), 2.07-1.99 (m,1H), 1.66-1.46 (m, 1H).

Example 1.20. Procedure T Example 1.20.1.(S)-2-((R)-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)-pyrrolidine(I-141) and(S)-2-((S)-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)-pyrrolidine(I-142)

(a).4-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)(hydroxy)methyl)benzo[d][1,3]dioxole-5-carboxylicacid

To a solution of benzo[d][1,3]dioxole-5-carboxylic acid (3.32 g, 20mmol) in tetrahydrofuran (30 mL) at −78° C. was added n-butyllithium inn-hexane (2.5 M, 17.5 mL, 44.0 mmol) dropwise over a period of 15 min.The reaction temperature was allowed to rise to −20° C. slowly. Themixture was stirred at this temperature for 1 h and cooled to −78° C.again. To the mixture was added a solution of (S)-tert-butyl2-formylpyrrolidine-1-carboxylate (5.97 g, 15 mmol) in tetrahydrofuran(5 mL) dropwise over a period of 5 min. The reaction mixture was stirredfor 6 h and then quenched with water (100 mL) at −78° C. The mixture waswashed with ethyl acetate (3×50 mL) and the combined organic phase wasextracted with water (50 mL). The combined aqueous layers were adjustedto pH=5 carefully with 0.5 M HCl solution at 0° C., extracted withdichloromethane (3×50 mL), dried over sodium sulfate and concentrated invacuo to give crude 4-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)(hydroxy)methyl)benzo[d][1,3]dioxole-5-carboxylic acid as a yellow oil(5.5 g, purity ca. 50%); MS (ESI): m/z=366 [M+H]⁺.

(b). (2S)-tert-butyl2-(6-oxo-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrroledine-1-carboxylate

To a solution of4-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)(hydroxy)methyl)benzo[d][1,3]dioxole-5-carboxylic acid (5.5 g, Purity: 50%, 7.52 mmol)in methanol (100 mL) was added 4 M HCl/1,4-dioxane (2.74 g, 75.2 mmol).The reaction mixture was stirred at room temperature for 16 h andconcentrated to give a residue. To the residue was added water (30 mL),tetrahydrofuran (30 mL), sodium bicarbonate (2.48 g, 29.6 mmol), anddi-tert-butyl dicarbonate (3.23 g, 14.8 mmol). The reaction mixture wasstirred at room temperature for 3 h and then extracted with ethylacetate (3×60 mL). The combined organic layers were dried over sodiumsulfate and concentrated in vacuo. The crude product was purified bysilica gel column chromatography (eluted with petroleum ether:ethylacetate=3:1) to give (2S)-tert-butyl2-(6-oxo-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine-1-carboxylate as a white solid (2.4 g). MS (ESI): m/z=292[M-55]⁺.

(c) (2S)-tert-butyl2-(hydroxy(5-(hydroxymethyl)benzo[d][1,3]dioxol-4-yl)methyl)pyrrolidine-1-carboxylate

To a solution of (2S)-tert-butyl2-(6-oxo-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine-1-carboxylate(2.1 g, 6.04 mmol) in tetrahydrofuran (100 mL) at 0° C. was addedlithium aluminium hydride (229 mg, 6.04 mmol) in portions. The reactionwas stirred at 0° C. for 1 h and then quenched with water (0.5 mL in 10mL tetrahydrofuran, dropwise at 0° C. over 5 mins) and then 15% sodiumhydroxide solution (0.5 mL). The mixture was stirred at 0° C. for 30 minand filtered through celite. The filtered cake was washed withdichloromethane (200 mL). The combined filtrate was concentrated to givea residue which was diluted with brine (50 mL), extracted with ethylacetate (3×100 mL). The organic layers were dried over sodium sulfateand concentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (eluted with petroleum ether:ethyl acetate=1:1) togive (2S)-tert-butyl2-(hydroxy(5-(hydroxymethyl)benzo[d][1,3]dioxol-4-yl)methyl)pyrrolidine-1-carboxylate as a white solid (2.0 g). MS (ESI): m/z=352[M+H]⁺.

(d). (2S)-tert-butyl2-(6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine-1-carboxylate

To a solution of (2S)-tert-butyl2-(hydroxy(5-(hydroxymethyl)benzo[d][1,3]dioxol-4-yl)methyl)pyrrolidine-1-carboxylate(1.9 g, 5.40 mmol) in tetrahydrofuran (120 mL) at −78° C. was addedn-butyllithium in n-hexane (2.5 M, 2.37 mL, 5.94 mmol). The reaction wasstirred at this temperature for 30 min. Then a solution of4-methylbenzene-1-sulfonyl chloride (1.13 g, 5.94 mmol) intetrahydrofuran (12 mL) was added. After the reaction mixture wasstirred at this temperature for 1 h, a solution of n-butyllithium inn-hexane (2.5 M, 2.37 mL, 5.94 mmol) was added. The mixture was allowedto warm to room temperature slowly, stirred at room temperature for anadditional 16 h and then quenched with water (150 mL) at 0° C. It wasextracted with ethyl acetate (3×100 mL) and the organic layers weredried over sodium sulfate and concentrated in vacuo. The crude productwas purified by Prep-TLC (eluted with petroleum ether:ethyl acetate=4:1)to give (2S)-tert-butyl2-(6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine-1-carboxylateas a yellow oil (680 mg). MS (ESI): m/z=334 [M+H]⁺.

(e).(S)-2-((R)-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine(I-141) and(S)-2-((S)-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine(I-142)

To a solution of (2S)-tert-butyl 2-(6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine-1-carboxylate (1.1 g, 3.3 mmol) indichloromethane (10 mL) was added 4 M hydrochloric acid/1,4-dioxanesolution (4 M, 2 mL, 8 mmol). The mixture was stirred at roomtemperature for 6 h and concentrated in vacuo to give a residue, whichwas washed with petroleum ether (50 mL), followed by ethyl acetate (5mL) to give the hydrochloride salt of(2S)-2-(6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine asa yellow solid (0.7 g). This mixture of two diastereoisomers wasseparated by Chiral HPLC (Co-Solvent: MeOH (0.5% NH₄OH), Column: AS-H4.6×250 mm 5 μm) to give(S)-2-((R)-6,8-dihydroisobenzofuro[4,5-d][1,3]dioxol-8-yl)pyrrolidine(I-141, 282 mg colorless oil) and(S)-2-((S)-6,8-dihydroisobenzofuro[4,5-d][1,3]dioxol-8-yl)pyrrolidine(I-142, 124 mg colorless oil).

(S)-2-((R)-6,8-dihydroisobenzofuro[4,5-d][1,3]dioxol-8-yl)pyrrolidine(I-141): MS (ESI): m/z 233 [M+H]⁺; ¹HNMR (HCl salt, 400 MHz, MeOD): δ6.87-6.89 (d, J=8 Hz, 1H), 6.78-6.80 (d, J=8 Hz, 1H), 6.01-6.04 (dd,J=11.6 Hz, 2H), 5.61-5.61 (d, J=2 Hz, 1H), 4.90-5.18 (m, 2H), 4.04-4.09(m, 1H), 3.31-3.34 (m, 1H), 1.74-2.07 (m, 4H).

(S)-2-((S)-6,8-dihydroisobenzofuro[4,5-d][1,3]dioxol-8-yl)pyrrolidine(I-142): MS (ESI): m/z 233 [M+H]⁺, ¹HNMR (HCl salt, 400 MHz, MeOD): δ6.88-6.90 (d, J=8 Hz, 1H), 6.80-6.82 (d, J=8 Hz, 1H), 6.02-6.06 (dd,J=15.2 Hz, 2H), 5.40-5.41 (d, J=4 Hz, 1H), 5.16-5.19 (d, J=12 Hz, 1H),5.02-5.04 (d, J=8 Hz, 1H), 3.87-3.91 (m, 1H), 3.25-3.36 (m, 2H),2.28-2.31 (m, 1H), 2.06-2.17 (m, 3H).

Example 1.21. Procedure U. Certain Provided Compounds were MadeFollowing a Procedure Exemplified by Example 1.21.1 Example 1.21.1.(S)-2-((1R,4S)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-137) and(S)-2-((1R,4R)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-138)

(a). (2S)-tert-butyl2-(4-chloro-6-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate

To a solution of 2-chloro-2-(3-fluorophenyl)ethanol (50 g, 287 mmol) indichloromethane (300 ml) in ice salt bath was addedtrifluoromethanesulfonic acid (129 g, 861 mmol) and (S)-tert-butyl2-formylpyrrolidine-1-carboxylate (114 g, 574 mmol) dropwise (innertemperature was kept <−5° C.). After the addition, the mixture wasstirred at room temperature for 3 h and was then basified with sodiumhydroxide (20% aq.) to pH=10. Di-tert-butyl dicarbonate (188 g, 861mmol) was added. The mixture was stirred at room temperature for 3 h,quenched with water (300 mL), and extracted with dichloromethane (200mL×2). The combined organic layers were dried and concentrated in vacuoto give a residue, which was purified by silica gel chromatographyeluted with petroleum ether:ethyl acetate=10:1 to give the desiredproduct (65 g) as a yellow oil.

(b). (2S)-tert-butyl2-(6-fluoro-4-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate

To a solution of (2S)-tert-butyl2-(4-chloro-6-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate (50 g,140.8 mmol) in tetrahydrofuran/water (200 mL, 1:1) was added silvernitrate (119.7 g, 704 mmol). The mixture was heated to reflux for 4 h.Upon cooling to room temperature, the mixture was extracted with ethylacetate (200 mL×3) and the organic layers were dried and concentrated invacuo to give a residue. To the residue was added acetic acid (200 mL)and zinc powder (45.8 g, 704 mmol) at room temperature. The mixture wasstirred at room temperature for 2 h and then filtered over celit. Thefiltrate was evaporated in vacuo to give an oil, which was dissolved inwater (500 mL) and extracted with ethyl acetate (200 mL). The organiclayers were washed with sodium bicarbonate (aq. Sat.), dried andconcentrated in vacuo to give the crude product which was purified byflash column chromatography with petroleum ether:ethyl acetate=2:1 toprovide (2S)-tert-butyl2-(6-fluoro-4-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate (35.0 g)as a yellow oil.

(c). (2S)-tert-butyl2-(4,6-difluoroisochroman-1-yl)pyrrolidine-1-carboxylate

To a solution of (2S)-tert-butyl 2-(6-fluoro-4-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate (30 g, 88.9 mmol) in dichloromethane (60 mL)in ice salt bath was added diethylaminosulfurtrifluoride (21.5 g, 133mmol) dropwise. The mixture was stirred at this temperature for 1 h andthen poured into saturated aqueous sodium bicarbonate (300 mL). Theresulting biphasic mixture was transferred to a separatory funnel. Thelayers were separated and the water phase was extracted withdichloromethane (2×200 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresulting oil was purified by flash column chromatography with agradient elution of petroleum ether:ethyl acetate=10:1 to provide(2S)-tert-butyl 2-(4,6-difluoroisochroman-1-yl)pyrrolidine-1-carboxylate(16 g) as a yellow oil.

(d). (S)-2-((1R,4S)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-137) and(S)-2-((1R,4R)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-138)

To a solution of (2S)-tert-butyl2-(4,6-difluoroisochroman-1-yl)pyrrolidine-1-carboxylate (5.8 g, 17.1mmol) in dichloromethane (L) was added trifluoroacetic acid (30 mL). Themixture was stirred at room temperature for 3 h and then evaporated invacuo to give the crude product, which was purified by Prep-HPLC,followed by chrial separation: Column: AY-H (250×4.6 mm 5 μm); MobilePhase: n-Hexane (0.1% DEA):EtOH (0.1% DEA)=90:10 to give(S)-2-((1R,4S)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-137, 900 mg)and (S)-2-((1R,4R)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-138, 860mg).

(S)-2-((1R,4S)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-137): MS(ESI): m/z=240[M+H]⁺; ¹H NMR (HCl salt, 400 MHz, MeOD): δ 7.35˜7.30 (m,1H), 7.20˜7.16 (m, 1H), 5.81˜5.65 (m, 1H), 5.24 (s, 1H), 4.51˜4.48 (m,1H), 4.41˜4.36 (m, 1H) 3.75˜3.69 (m, 1H), 3.37˜3.31 (m, 2H), 2.06˜2.1.91(m, 2H), 1.83˜1.68 (m, 2H).

(S)-2-((1R,4R)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-138): MS(ESI): m/z=240[M+H]⁺; 1H NMR (HCl salt, 400 MHz, MeOD): δ 7.38-7.42 (m,1H), 7.23-7.32 (m, 2H), 5.33-5.45 (m, 1H), 5.16-5.18 (m, 1H), 4.44-4.51(m, 2H), 3.90-4.03 (m, 1H), 3.34-3.42 (m, 2H), 1.78-2.07 (m, 4H).

Example 1.21.2. (2S)-2-((1R)-4,6-difluoroisochroman-1-yl)azetidine(I-135) and (2S)-2-((1S)-4,6-difluoroisochroman-1-yl)azetidine (I-136)

(2S)-2-((1R)-4,6-difluoroisochroman-1-yl)azetidine (I-135) and(2S)-2-((1S)-4,6-difluoroisochroman-1-yl)azetidine (136) were preparedusing a procedure analogous to that described in Example 1.21.1, butusing (S)-tert-butyl 2-formylazetidine-1-carboxylate in place of(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

(2S)-2-((1R)-4,6-difluoroisochroman-1-yl)azetidine (I-135): MS (ESI):m/z=224 [M+H]⁺; ¹H NMR (HCl salt, 400 MHz, MeOD): δ 7.35˜7.32 (m, 1H),7.25˜7.22 (m, 1H), 7.18˜7.13 (m, 1H) 5.89˜5.72 (m, 1H), 5.17˜5.12 (m,2H), 4.62˜4.57 (m, 1H), 4.03˜3.77 (m, 3H) 2.32˜2.26 (m, 2H).

(2S)-2-((1S)-4,6-difluoroisochroman-1-yl)azetidine (136): MS (ESI):m/z=224 [M+H]⁺; ¹H NMR (HCl slat, 400 MHz, MeOD): δ 7.35˜7.30 (m, 2H),7.22˜7.17 (m, 1H), 5.72˜5.61 (m, 1H), 5.11˜5.08 (m, 2H), 4.49˜4.43 (m,1H), 4.11˜4.04 (m, 1H), 3.93˜3.81 (m, 2H), 2.98˜2.94 (m, 1H), 2.60˜2.56(m, 1H).

Example 1.22. Procedure V Example 1.22.1.(1R)-6-fluoro-1-((S)-pyrrolidin-2-yl)isochroman-4-ol (I-134)

To a solution of (S)-tert-butyl2-((R)-6-fluoro-4-hydroxyisochroman-1-yl) pyrrolidine-1-carboxylate (2.2g, 6.5 mmol, prepared in Example 21.1) in dichloromethane (20 mL) wasadded trifluoroacetic acid (6 mL). The mixture was stirred at roomtemperature for 3 h and then evaporated in vacuo to get a residue, whichwas purified by Prep-HPLC to give(1R)-6-fluoro-1-((S)-pyrrolidin-2-yl)isochroman-4-ol (650 mg).m/z=238[M+H]⁺. ¹H NMR (HCl salt, 400 MHz, MeOD): δ 7.36˜7.33 (m, 1H),7.28˜7.25 (m, 1H), 7.08˜7.03 (m, 1H) 5.22 (s, 1H), 4.82˜4.78 (m, 1H),4.39˜4.35 (m, 1H) 4.30˜4.26 (m, 1H), 3.46 (t, J=10.4 Hz, 1H), 3.38˜3.28(m, 2H), 2.05˜1.91 (m, 2H), 1.77˜1.68 (m, 2H).

Example 2. Biological Assays Example 2.1 In Vitro Assay

Certain compounds were tested by in vitro binding assays using standardprocedures. Table 2 shows the membrane source, radioligand, ligand usedto define non-specific binding and incubation conditions for eachreceptor. These receptors and assays are well known to those skilled inthe art, as exemplified by the following: Abramovitz, M. et al. (2000),Biochem. Biophys. Acta., 1483: 285-293 (EP4, IP (PGI₂)); Aharony, D. etal. (1993), Mol. Pharmacol., 44: 356-363 (NK2); Ardati, A. et al.(1997), Mol. Pharmacol., 51: 816-824 (NOP (ORL1)); Bignon, E. et al.(1999), J. Pharmacol. Exp. Ther. 289: 742-751 (CCK₁ (CCK_(A)));Bloomquist, B. T. et al. (1998), Biochem. Biophys. Res. Commun., 243:474-479 (GAL₂); Brockhaus, M. et al. (1990), Proc. Natl. Acad. Sci.U.S.A., 87: 3127-3131 (TNF-α); Brown, G. B. (1986), J. Neurosci., 6:2064-2070 (Na+ channel (site 2)); Buchan, K. W. et al. (1994), Brit. J.Pharmacol., 112: 1251-1257 (ETA); Cesura, A. M. et al. (1990), Mol.Pharmacol., 37: 358-366 (MAO-A); Choi, D. S. et al. (1994), FEBS Lett.,352: 393-399 (5-HT2B); Clark, A. F. et al. (1996), Invest. Ophtalmol.Vis. Sci., 37: 805-813 (GR); Couvineau, A. et al. (1985), Biochem. J.,231: 139-143 (VPAC₁ (VIP₁)); Dorje, F. et al. (1991), J. Pharmacol. Exp.Ther., 256: 727-733 (M1, M2, M3, M4); Ferry, G. et al. (2001), Eur. J.Pharmacol., 417: 77-89 (PPARγ); Fuchs, S. et al. (2001), Mol. Med., 7:115-124 (ETB); Fuhlendorff, J. et al. (1990), Proc. Natl. Acad. Sci.U.S.A., 87: 182-186 (Y2); Ganapathy M E. et al. (1999), J. Pharmacol.Exp. Ther., 289: 251-260 (sigma (non-selective)); Gopalakrishnan, M. etal. (1996), J. Pharmacol. Exp. Ther., 276: 289-297 (N neuronal α4β2);Greengrass, P. and Bremner, R. (1979), Eur. J. Pharmacol., 55: 323-326(α₁ (non-selective)); Grandy, D. K. et al. (1989), Proc. Natl. Acad.Sci. U.S.A., 86: 9762-9766 (D25); Guard, S. et al. (1993), Eur. J.Pharmacol., 240: 177-184 (BB (non-selective)); Heuillet, E. et al.(1993), J. Neurochem., 60: 868-876 (NK1, P2X); Hope, A. G. et al.(1996), Brit. J. Pharmacol., 118: 1237-1245 (5-HT3); Hoyer, D. et al.(1985), Eur. J. Pharmacol., 118: 1-12 (5-HT1B); Hugues, M. et al.(1982), J. Biol. Chem., 257: 2762-2769 (5-HT2A, SKCa channel); Joseph,S. S. et al. (2004), Naun.-Sch. Arch. Pharm., 369: 525-532 (12); Le, M.T. et al. (2005), Eur. J. Pharmacol., 513: 35-45 (AT1); Le Fur, G. etal. (1983), Life Sci., 33: 449-457) (BZD (peripheral); Lee, Y. M. et al.(1993), J. Biol. Chem., 268: 8164-8169 (CCK₂ (CCK_(B))); Leurs, R. etal. (1994), Brit. J. Pharmacol., 112: 847-854 (H2); Levin, M. C. et al.(2002), J. Biol. Chem., 277: 30429-30435 (11); Lewin, A. H. et al.(1989), Mol. Pharmacol., 35: 189-194 (Cl-channel (GABA-gated)); Lukas,R. J. (1986), J. Neurochem., 46: 1936-1941 (N muscle-type); Luthin, D.R. et al. (1995), Mol. Pharmacol., 47: 307-313; (A2A); Mackenzie, R. G.et al. (1994), Eur. J. Pharmacol., 266: 79-85 (D3); Mulheron, J. G. etal. (1994), J. Biol. Chem., 269: 12954-12962 (5-HT1A); Meng, F. et al.(1993), Proc. Natl. Acad. Sci. U.S.A., 90: 9954-9958 (κ (KOP)); Monsma,F. J. et al. (1993), Mol. Pharmacol., 43: 320-327 (5-HT6); Neote, K. etal. (1993), Cell, 72: 415-425 (CCR1); Pacholczyk, T. et al. (1991),Nature, 350: 350-354 (sst (non-selective, norepinephrine transporter));Peralta, E. G. et al. (1987), Embo. J., 6: 3923-3929 (M3); Pristupa, Z.B. et al. (1994), Mol. Pharmacol., 45: 125-135 (dopamine transporter);Pruneau, D. et al. (1998), Brit. J. Pharmacol., 125: 365-372 (B2); Rees,S. et al. (1994), FEBS Lett., 355: 242-246 (5-HT5a); Reynolds, I. J. etal. (1986), J. Pharmacol. Exp. Ther., 237: 731-738 (Ca2+ channel (L,verapamil site)); Rinaldi-Carmona, M. et al. (1996), J. Pharmacol. Exp.Ther., 278: 871-878 (CB1); Salvatore, C. A. et al. (1993), Proc. Natl.Acad. Sci. U.S.A., 90: 10365-10369 (A3); Sarau, H. M. et al. (1997), J.Pharmacol. Exp. Ther., 281: 1303-1311 (NK3); Schioth, H. B. et al.(1997), Neuropeptides, 31: 565-571 (MC4); Sharples, C. G. V. et al.(2000), J. Neurosci., 20: 2783-2791 (N neuronal α7); Shen, Y. et al.(1993), J. Biol. Chem., 268: 18200-18204 (5-HT7); Sills, M. A. et al.(1991), Eur. J. Pharmacol., 192: 19-24 (NMDA); Simon, J. et al. (1995),Pharmacol. Toxicol., 76: 302-307 (P2Y); Simonin, F. et al. (1994), Mol.Pharmacol., 46: 1015-1021 (δ₂ (DOP)); Smit, M. J. et al. (1996), Brit.J. Pharmacol., 117: 1071-1080 (H1); Sorensen, R. G. and Blaustein, M. P.(1989), Mol. Pharmacol., 36: 689-698 (KV channel); Speth, R. C. et al.(1979), Life Sci., 24: 351-358 (BZD (central)); Stam, N. J. et al.(1994), Eur. J. Pharmacol., 269: 339-348 (5-HT2C); Sullivan, K. A. etal. (1997), Biochem. Biophys. Res. Commun., 233: 823-828 (GAL₁); Tahara,A. et al. (1998), Brit. J. Pharmacol., 125: 1463-1470 (V1a); Tatsumi, M.et al. (1999), Eur. J. Pharmacol., 368: 277-283 (5-HT transporter);Townsend-Nicholson, A. and Schofield, P. R. (1994), J. Biol. Chem., 269:2373-2376 (A1); Tsuji, A. et al. (1988), Antimicrob. Agents Chemother.,32: 190-194 (GABA (non-selective)); Tsuzuki, S. et al. (1994), Biochem.Biophys. Res. Commun., 200: 1449-1454 (AT2); Uhlen, S. and Wikberg, J.E. (1991), Pharmacol. Toxicol., 69: 341-350 (α₂ (non-selective)); VanTol, H. H. M. et al. (1992), Nature, 358: 149-152 (D_(4.4)); Vignon, J.et al. (1986), Brain Res., 378: 133-141 (PCP); Vita, N. et al. (1993),FEBS Lett., 317: 139-142 (NTS₁ (NT₁)); White, J. R. et al. (1998), J.Biol. Chem., 273: 10095-10098 (CXCR2 (IL-8B), μ (MOP)); Wieland, H. A.et al. (1995), J. Pharmacol. Exp. Ther., 275: 143-149 (Y1);Witt-Enderby, P. A. and Dubocovich, M. L. (1996), Mol. Pharmacol., 50:166-174 (MT₁ (ML_(1A))); Zhou, Q. Y. et al. (1990), Nature, 347: 76-80(D1).

Briefly, a membrane was incubated with a radioligand in the presence andabsence of a test compound under the relevant condition, prior tofiltration and washing. The amount of the radioligand bound to amembrane was determined using liquid scintillation counting. Totalbinding (the binding of a radioligand to both receptor and non-receptorsites) was determined by incubating a membrane with a radioligand alone.Non-specific binding (binding to non-receptor sites) of a radioligandwas determined by incubating a membrane in the presence of a saturatingconcentration of an unlabeled ligand (the ligand used to definenon-specific binding). Specific binding (binding to receptor sites only)was calculated by subtracting non-specific binding from total binding.

TABLE 2 Assay Source Ligand Conc. (nM) Non Specific Incubation A1 human[3H]DPCPX 1 DPCPX 60 min recombinant (1 μM) RT (CHO cells) A2A human[3H]CGS 21680 6 NECA 120 min recombinant (10 μM) RT (HEK-293 cells) A3human [125I]AB-MECA 0.15 IB-MECA 120 min recombinant (1 μM) RT (HEK-293cells) α₁ (non- rat cerebral [3H]prazosin 0.25 prazosin 60 minselective) cortex (0.5 μM) RT α₂ (non- rat cerebral [3H]RX 821002 0.5(−)epinephrine 60 min selective) cortex (100 μM) RT β1 human [3H](−)CGP12177 0.3 alprenolol 60 min recombinant (50 μM) RT (HEK-293 cells) β2human [3H](−)CGP 12177 0.3 alprenolol 120 min recombinant (50 μM) RT(CHO cells) AT1 human [125I][Sar1, Ile8]-AT-II 0.05 angiotensin-II 120min recombinant (10 μM) 37° C. (HEK-293 cells) AT2 human [125I]CGP42112A 0.01 angiotensin-II 4 hr recombinant (1 μM) 37° C. (HEK-293cells) BZD (peripheral) rat heart [3H]PK 11195 0.2 PK 11195 15 min (10μM) RT BB (non- rat cerebral [125I][Tyr4]bombesin 0.01 bombesin 60 minselective) cortex (1 μM) RT B2 human [3H]bradykinin 0.3 bradykinin 60min recombinant (1 μM) RT (CHO cells) CB1 human [3H]CP 55940 0.5 WIN55212-2 120 min recombinant (10 μM) 37° C. (CHO cells) CCK₁ (CCK_(A))human [125I]CCK-8s 0.08 CCK-8s 60 min recombinant (1 μM) RT (CHO cells)CCK₂ (CCK_(B)) human [125I]CCK-8s 0.08 CCK-8s 60 min recombinant (1 μM)RT (CHO cells) D1 human [3H]SCH 23390 0.3 SCH 23390 60 min recombinant(1 μM) RT (CHO cells) D2S human [3H]methylspiperone 0.3 (+)butaclamol 60min recombinant (10 μM) RT (HEK-293 cells) D3 human [3H]methylspiperone0.3 (+)butaclamol 60 min recombinant (10 μM) RT (CHO cells) D_(4.4)human [3H]methylspiperone 0.3 (+)butaclamol 60 min recombinant (10 μM)RT (CHO cells) ETA human [125I]endothelin-1 0.03 endothelin-1 120 minrecombinant (100 nM) 37° C. (CHO cells) ETB human [125I]endothelin-10.03 endothelin-1 120 min recombinant (0.1 μM) 37° C. (CHO cells) GABArat cerebral [3H]GABA 10 GABA 60 min (non-selective) cortex (100 μM) RTGAL₁ human [125I]galanin 0.1 galanin 80 min recombinant (1 μM) RT(HEK-293 cells) GAL₂ human [125I]galanin 0.05 galanin 120 minrecombinant (1 μM) RT (CHO cells) CXCR2 (IL-8B) human [125I]IL-8 0.025IL-8 60 min recombinant (30 nM) RT (HEK-293 cells) CCR1 human[125I]MIP-1α 0.01 MIP-1α 120 min recombinant (100 nM) RT (HEK-293 cells)TNF-α U-937 cells [125I]TNF-α 0.1 TNF-α 120 min (10 nM) 4° C. H1 human[3H]pyrilamine 1 pyrilamine 60 min recombinant (1 μM) RT (HEK-293 cells)H2 human [125I]APT 0.075 tiotidine 120 min recombinant (100 μM) RT (CHOcells) MC4 human [125I]NDP-α-MSH 0.05 NDP-α-MSH 120 min recombinant (1μM) 37° C. (CHO cells) MT₁ (ML_(1A)) human [125I]2- 0.01 melatonin 60min recombinant iodomelatonin (1 μM) RT (CHO cells) M1 human[3H]pirenzepine 2 atropine 60 min recombinant (1 μM) RT (CHO cells) M2human [3H]AF-DX 384 2 atropine 60 min recombinant (1 μM) RT (CHO cells)M3 human [3H]4-DAMP 0.2 atropine 60 min recombinant (1 μM) RT (CHOcells) M4 human [3H]4-DAMP 0.2 atropine 60 min recombinant (1 μM) RT(CHO cells) M5 human [3H]4-DAMP 0.3 atropine 60 min recombinant (1 μM)RT (CHO cells) NK1 U-373MG [125I]BH-SP 0.15 [Sar9, Met(O2)11]-SP 60 mincells (1 μM) RT (endogenous) NK2 human [125I]NKA 0.1 [Nleu10]-NKA (4-10)60 min recombinant (300 nM) RT (CHO cells) NK3 human [3H]SR 142801 0.4SB 222200 120 min recombinant (10 μM) RT (CHO cells) Y1 SK-N-MC cells[125I]peptide YY 0.025 NPY 120 min (endogenous) (1 μM) 37° C. Y2 KAN-TScells [125I]peptide YY 0.015 NPY 60 min (1 μM) 37° C. NTS₁ (NT₁) human[125I]Tyr3- 0.05 neurotensin 60 min recombinant neurotensin (1 μM) 4° C.(CHO cells) N neuronal α4β2 SH-SY5Y cells [3H]cytisine 0.6 nicotine 120min (human (10 μM) 4° C. recombinant) N neuronal α7 SH-SY5Y cells[125I]α-bungarotoxin 0.05 α-bungarotoxin 120 min (human (1 μM) 37° C.recombinant) N muscle-type TE671 cells [125I]α-bungarotoxin 0.5α-bungarotoxin 120 min (endogenous) (5 μM) RT δ₂ (DOP) human [3H]DADLE0.5 naltrexone 120 min recombinant (10 μM) RT (CHO cells) κ (KOP) rat[3H]U 69593 1 naloxone 60 min recombinant (10 μM) RT (CHO cells) μ (MOP)human [3H]DAMGO 0.5 naloxone 120 min recombinant (10 μM) RT (HEK-293cells) NOP (ORL1) human [3H]nociceptin 0.2 nociceptin 60 min recombinant(1 μM) RT (HEK-293 cells) PPARγ human [3H]rosiglitazone 5 rosiglitazone120 min recombinant (10 μM) 4° C. (E. coli) EP4 human [3H]PGE2 0.5 PGE2120 min recombinant (10 μM) RT (HEK-293 cells) IP (PGI₂) human[3H]iloprost 6 iloprost 60 min recombinant (10 μM) RT (HEK-293 cells)P2Y rat cerebral [35S]dATPαS 10 dATPαS 60 min cortex RT 5-HT1A human[3H]8-OH-DPAT 0.3 8-OH-DPAT 60 min recombinant (10 μM) RT (HEK-293cells) 5-HT1B rat cerebral [125I]CYP 0.1 serotonin 120 min cortex (+30μM (10 μM) 37° C. isoproterenol) 5-HT2A human [3H]ketanserin 0.5ketanserin 60 min recombinant (1 μM) RT (HEK-293 cells) 5-HT2B human[125I](±)DOI 0.2 (±)DOI 60 min recombinant (1 μM) RT (CHO cells) 5-HT2Chuman [3H]mesulergine 1 RS 102221 120 min recombinant (10 μM) 37° C.(HEK-293 cells) 5-HT5a human [3H]LSD 1.5 serotonin 120 min recombinant(100 μM) 37° C. (HEK-293 cells) 5-HT6 human [3H]LSD 2 serotonin 120 minrecombinant (100 μM) 37° C. (CHO cells) 5-HT7 human [3H]LSD 4 serotonin120 min recombinant (10 μM) RT (CHO cells) sigma (non- Jurkat cells[3H]DTG 10 Haloperidol 120 min selective) (endogenous) (10 μM) RT sst(non- AtT-20 cells [125I]Tyr11- 0.05 somatostatin-14 60 min selective)somatostatin-14 (300 nM) 37° C. GR IM-9 cells [3H]dexamethasone 1.5triamcinolone 6 hr (cytosol) (10 μM) 4° C. VPAC₁ (VIP₁) human [125I]VIP0.04 VIP 60 min recombinant (1 μM) RT (CHO cells) V1a human [3H]AVP 0.3AVP 60 min recombinant (1 μM) RT (CHO cells) BZD (central) rat cerebral[3H]flunitrazepam 0.4 diazepam 60 min cortex (3 μM) 4° C. NMDA ratcerebral [3H]CGP 39653 5 L-glutamate 60 min cortex (100 μM) 4° C. PCPrat cerebral [3H]TCP 10 MK 801 120 min cortex (10 μM) 37° C. P2X raturinary [3H]α,β-MeATP 3 α,β-MeATP 120 min bladder (10 μM) 4° C. 5-HT3human [3H]BRL 43694 0.5 MDL 72222 120 min recombinant (10 μM) RT (CHOcells) Ca2+ channel rat cerebral [3H]D888 3 D 600 120 min (L, verapamilcortex (10 μM) RT site) KV channel rat cerebral [125I]α-dendrotoxin 0.01α-dendrotoxin 80 min cortex (50 nM) RT SKCa channel rat cerebral[125I]apamin 0.007 apamin 60 min cortex (100 nM) 4° C. Na+ channel ratcerebral [3H]batrachotoxinin 10 veratridine 60 min (site 2) cortex (300μM) 37° C. Cl− channel rat cerebral [35S]TBPS 3 picrotoxinin 120 min(GABA-gated) cortex (20 μM) RT norepinephrine human [3H]nisoxetine 1desipramine 120 min transporter recombinant (1 μM) 4° C. (CHO cells)dopamine human [3H]BTCP 4 BTCP 120 min transporter recombinant (10 μM)4° C. (CHO cells) 5-HT transporter human [3H]imipramine 2 imipramine 60min recombinant (10 μM) RT (CHO cells) MAO-A rat cerebral [3H]Ro 41-104910 clorgyline 60 min cortex (1 μM) 37° C.

Table 3 shows certain compounds and receptors for which the testcompound's specific binding (measured by percentage inhibition) wasgreater than 50%.

TABLE 3 Compound Receptor (percent inhibition) I-1 α1 (55%); α2 (95%);5HT1a (79%); 5HT2b (79%); 5HT2c (63%); 5HT7 (88%) I-5 α1 (59%); α2(96%); GABA (57%); KOP (71%); 5HT1a (52%); 5HT2b (72%); 5HT7 (60%) I-95HT7 (80%); α1 (73%); α2 (91%); 5HT1a (77%); 5HT2b (76%); 5HT2c (61%)I-29 α1 (69%); α2 (97%); k (89%); 5HT1a (71%); 5HT2b (80%); 5HT2c (67%);5HT7 (52%) I-83 α2 (77%); 5HT1a (87%); 5HT2b (83%); 5HT2c (64%); 5HT5a(58%); 5HT7 (99%) I-90 α1 (64%); α2 (71%); 5HT1a (64%); 5HT2b (77%);5HT2c (59%); 5HT7 (96%); Sert (80%); sigma (63%) I-94 α1 (72%); κ (67%);5HT2b (76%); 5HT7 (74%); sigma (85%) I-96 α1 (81%); α2 (81%); 5HT2b(58%); 5HT7 (69%); M4 (53%)

Example 2.2. Neuropharmacological Assay (SmartCube™)

In order to further demonstrate the utility of the provided compounds totreat neurological and psychiatric diseases and disorders, exemplarycompounds were evaluated using the neuropharmacological screen describedin S. L. Roberds et al., Front. Neurosci. 2011 Sep. 9; 5:103 (doi:10.3389/fnins.2011.00103) (“Roberds”). As reported in Roberds, becausepsychiatric diseases generally result from disorders of cell-cellcommunication or circuitry, intact systems are useful in detectingimprovement in disease-relevant endpoints. These endpoints are typicallybehavioral in nature, often requiring human observation andinterpretation. To facilitate testing of multiple compounds forbehavioral effects relevant to psychiatric disease, PsychoGenics, Inc.(Tarrytown, N.Y., “PGI”) developed SmartCube™, an automated system inwhich behaviors of compound-treated mice are captured by digital videoand analyzed with computer algorithms. (D. Brunner et al., Drug Discov.Today 2002, 7:S107-S112). PGI Analytical Systems uses data fromSmartCube™ to compare the behavioral signature of a test compound to adatabase of behavioral signatures obtained using a large set of diversereference compounds. (The composition of the database as well asvalidation of the method is further described in Roberds). In this way,the neuropharmacological effects of a test compound can be predicted bysimilarity to major classes of compounds, such as antipsychotics,anxiolytics and antidepressants.

The SmartCube™ system produces an activity signature indicating theprobability that the activity of the test compound at the administereddose matches a given class of neuropharmacological agents. (See, e.g.,Roberds, FIGS. 2 and 3). The test compound is simultaneously comparedagainst multiple classes of agents; thus, a separate probability isgenerated for each behavioral effect measured (e.g., anxiolyticactivity, analgesic activity, etc.). In Table 4, these probabilities arereported for each behavioral effect measured as follows:

LOQ≤  +  <5%  5%≤ ++ <25% 25%≤ +++ <50% 50%≤ ++++where LOQ is the limit of quantification.

Provided compounds were dissolved in a mixture of Pharmasolve™(N-methyl-2-pyrrolidone), polyethylene glycol and propylene glycol, andwere injected i.p. 15 min. before the behavioral test. For eachcompound, injections were administered at 3 different doses. For eachbehavioral effect measured, results for the most efficacious dose(s) arepresented.

TABLE 4 Compound DP AX SD PS MS AD CE AG XG HA UN I-1 ++ ++ ++ +++ ++ +++ ++ + + ++ I-2 + ++ ++ ++ ++ + + + + + + I-3 +++ ++ ++ ++ ++ + ++++ + + +++ I-4 ++ +++ + ++ + + ++ ++ + + + I-5 ++ ++ + +++ ++ + ++++ + + +++ I-6 ++ ++ + ++ + + + + + + +++ I-7 ++ ++ + ++ + + ++ ++ + ++++ I-8 +++ ++ ++ +++ + + ++ + + + ++ I-9 ++ ++ ++ +++ ++ + ++ ++ + ++++ I-10 ++ ++ + ++ + + ++ ++ + + + I-11 ++ ++ + +++ + + ++ ++ + + ++I-12 ++ ++ + ++ + + + ++ + + ++++ I-13 +++ ++ + ++++ ++ + ++ ++ + + ++I-14 +++ ++ + +++ ++ + ++ ++ + + + I-15 ++ +++ + ++ + + ++ ++ + + + I-16++ ++ + +++ ++ + ++ + + + +++ I-17 +++ ++ + ++ + + ++ + + + + I-18 +++++ ++ +++ ++ + ++ ++ + + ++ I-19 + ++ + ++++ + + ++ + + + ++++ I-20 ++++ ++ ++++ ++ + ++ ++ + + +++ I-21 ++ ++ + ++ + + + ++ + + +++ I-22 +++++ + +++ + + ++ ++ + + + I-23 ++ ++ ++ +++ ++ + ++ +++ + + + I-24 +++ ++++ ++ ++ + ++ ++ + + + I-25 ++ ++ + ++ + + ++ +++ + + ++ I-26 +++ + + + + + + + + + I-27 ++ +++ + ++ ++ + ++ ++ + + + I-28 ++ +++ +++ + + + ++ + + ++ I-29 ++ +++ + ++ ++ + +++ ++ + + ++ I-30 ++ +++ +++++ + + ++ ++ + + + I-31 ++ +++ ++ +++ ++ + ++ ++ + + + I-32 ++ ++ +++++ + + ++ +++ + + + I-33 ++ ++ ++ +++ + + ++ + + + + I-34 ++ ++ ++++ + + ++ ++ + + +++ I-35 ++ ++ ++ +++ + + ++ + + + ++ I-36 ++ ++ + +++++ + ++ ++ + + ++ I-37 ++ ++ + ++ + + + + + + +++ I-38 ++ ++ + + + + +++ + + + I-39 + ++ + + + + ++ ++ + + ++ I-40 ++ ++ + +++ + + ++ + + + +I-41 +++ ++ ++ ++ ++ + ++ ++ + + + I-42 +++ ++ ++ ++ + + ++ ++ + + +I-43 ++ +++ + ++ + + ++ ++ + + + I-44 ++ +++ + +++ ++ + ++ ++ + + + I-45++ +++ + + + + + ++ + + + I-46 ++ ++ ++ ++++ + + ++ ++ + + + I-47 +++ + + + + + + + + + I-48 ++ ++ + ++ + + ++ +++ + + + I-49 ++ ++ ++ ++++ + ++ ++ + + ++ I-50 ++ +++ + ++ + + ++ ++ + + +++ I-51 + ++ + + + + +++ + + ++ I-52 ++ ++++ + ++ + + ++ ++ + + +++ I-53 + + + + + + + + + + +I-54 +++ +++ + ++ ++ + ++ ++ + + + I-55 + + + + + + + + + + + I-56 +++++ + ++ ++ ++ ++ +++ + + + I-57 + + + + + + + + + + + I-58 +++ ++ + ++++ + + ++ + + + I-59 ++ ++ + ++ ++ + ++ + + + + I-60 ++ ++ ++ +++ + + ++++ + + ++ I-61 ++ ++ + ++ ++ + + +++ ++ + + I-62 ++ ++ + ++ + + +++++ + + + I-63 + + + + + + + + + + + I-64 + ++ + + + + + + + + + I-65 ++++ ++ ++ + + ++ +++ + + + I-66 ++ ++ + +++ + + ++ ++ + + ++I-67 + + + + + + + + + + + I-68 + + + + + + + + + + + I-69 ++ ++ +++ + + ++ +++ + + + I-70 ++ +++ + + + + + ++ + + + I-71 ++ +++ + ++ ++ +++ + + + + I-72 + ++ + + + + + ++ ++ + +++ I-73 ++ ++ + + ++ + ++ ++ + ++++ I-74 ++ ++ ++ +++ + + ++ ++ + + + I-75 +++ ++ ++ ++ ++ + ++ + + + +I-76 ++ ++ + ++ + + + ++ + + + I-77 + ++ + + + + + + + + + I-78 ++ +++ +++ + + ++ ++ + + + I-79 ++ +++ + +++ ++ ++ ++ ++ + + + I-80 +++ ++ + ++++ + ++ ++ + + +++ I-81 ++ +++ +++ ++ + + ++ ++ + + + I-82 +++ ++ ++ ++++ + ++ ++ + + ++ I-83 ++ ++ + +++ ++ ++ +++ ++ + + + I-84 ++ ++ ++ ++++++ + + + + + + I-85 ++ ++ ++ +++ + + ++ + + + ++ I-86 ++ +++ ++ +++ + +++ +++ + + ++ I-87 ++ ++ + +++ + + + ++ + + ++ I-88 ++ +++ + ++ + + ++++ + + +++ I-89 +++ ++ + +++ ++ ++ ++ ++ + + + I-90 +++ +++ ++ ++ + + ++++ + + ++ I-91 ++ ++ ++ +++ + + ++ ++ + + ++ I-92 ++ ++ + +++ ++ + +++++ + + + I-93 +++ ++ ++ ++ + ++ ++ +++ + + ++ I-94 +++ ++ + +++ + + ++++ + + ++ I-95 ++ ++ + ++ + + ++ +++ + + + I-96 +++ ++ + +++ ++ + +++++ + + + I-97 ++ ++ ++ +++ ++ + ++ +++ + + + I-98 +++ ++ ++ +++++ + + + + + + I-99 +++ ++ ++ ++ + + ++ ++ + + + I-100 ++ ++ ++ +++ ++ ++++ ++ + + + I-101 ++ ++ + + + + + + + + + I-102 ++ +++ + ++ ++ + ++++ + + + I-103 ++ ++ ++ + + + + ++ + + +++ I-104 ++ ++ ++ + + + ++++ + + ++ I-105 ++ +++ ++ ++ + + ++ ++ + + ++++ I-106 + ++ + ++ + + +++++ + + + I-107 ++ +++ ++ +++ ++ + ++ ++ + + ++ I-108 ++ ++ ++ +++ + + ++++ + + ++ I-109 +++ ++ ++ ++ ++ + + ++ + + ++ I-110 ++ ++ ++ ++++ + + ++++ + + +++ I-111 ++ ++ ++ ++++ + + ++ ++ + + +++ I-112 ++ ++ + +++ + +++ + + + + I-113 +++ ++ ++ ++ + + ++ ++ + + + I-114 +++ ++ ++ ++ + + ++++ + + + I-115 ++ ++ ++ ++ + + ++ ++ + + +++ I-116 ++ ++ +++++ + + + + + + + I-117 ++ ++ + +++ + + ++ + + + + I-118 ++ +++ ++ +++++ + ++ ++ + + + I-119 ++ ++ + +++ + + ++ +++ + + + I-120 ++ ++ ++ ++++ + +++ ++ + + ++ I-121 ++ +++ ++ ++ + + ++ +++ + + ++ I-122 ++++ + + + + + + + + + I-123 + + + + + + + + + + +I-124 + + + + + + + + + + + I-125 ++++ ++ ++ + + + ++ ++ + + + I-126 +++++ ++ +++ + + ++ ++ + + ++ I-127 ++ ++ + ++ + + ++ ++ + + ++ I-128 ++++ + ++++ + + + ++ + + + I-134 + ++ + + + + + + + + + I-135 ++ ++ ++ +++++ + ++ ++ + + ++ I-137 ++ ++ ++ ++++ ++ + ++ ++ + + ++ I-138 ++ ++ ++++ + + + + + + ++ I-139 ++ ++ + +++ + + ++ + + + + I-140 ++ ++ +++ ++++ + +++ ++ + + ++ I-141 ++ ++ + ++ + ++ +++ ++ + ++ ++++ I-142 ++ +++ +++ + + ++ ++ + + ++ I-143 ++ ++ + ++ + + + ++ + + +++ I-144 +++ ++ + +++++ ++ ++ ++ + + +++ DP: anti-depressant; AX: anxiolytic; SD: sedativehypnotic; PS: anti-psychotic; MS: mood stabilizer; AD: ADHD; CE:cognitive enhancer; AG: analgesic; XG: anxiogenic; HA: hallucinogen; UN:uncharacterized CNS activity.

Some embodiments of the present invention are enumerated below. In suchpresentations, an embodiment reciting a “compound” with reference toanother enumerated embodiment either that itself explicitly recites “ora pharmaceutically acceptable salt thereof” or that refers ultimately toan enumerated embodiment that does, is intended to encompass both freecompounds and pharmaceutically acceptable salts thereof. As aconvention, the phrase “or a pharmaceutically acceptable salt thereof”is explicitly recited when the structural formula of the compound isexplicitly recited, but no difference in inclusion or exclusion ofpharmaceutically acceptable salts is thereby intended. For example, bothembodiments 1 and 6 are intended to encompass both the free compoundsand pharmaceutically acceptable salts thereof.

-   1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   A is

-   m is 0, 1, or 2;-   n1 is 1, 2, or 3;-   n2 is 0 or 1;-   n3 is 0 or 1;-   R is —H or C₁-C₃ alkyl;-   R^(a) is —H or C₁-C₃ alkyl;-   R¹, R², R³, and R⁴ are independently —H, halo, —OH, —NH₂, C₁-C₃    alkyl, —OR⁷, —NHR⁷, —N(R⁷)R⁷, —CN, phenyl, or 5- or 6-membered    heteroaryl, wherein:-   each instance of R⁷ independently is unsubstituted C₁-C₂ alkyl or    C₁-C₂ alkyl substituted with 1-3 halo,-   each instance of C₁-C₃ alkyl independently is unsubstituted or    substituted with 1-3 halo, and-   the phenyl or heteroaryl is unsubstituted or substituted with 1 or 2    groups independently selected from halo, —OH, —OCH₃, —OCF₃, —NH₂,    —NH(CH₃), —N(CH₃)₂, —CH₃, ethyl, —CF₃, and —CN,-   optionally wherein-   two adjacent instances of R¹, R², R³, and R⁴ together form    —O—CH₂—O—, —O—CH(CH₃)—O—, —O—C(CH₃)₂—O—, —O—CH₂—CH₂—O—, or    —O—C(CH₃)₂—C(CH₃)₂—O—;-   each instance of R⁵ independently is halo, —CH₃, or ethyl;-   each instance of R⁶ independently is halo, —CH₃, ethyl or —OH;-   w is 0, 1, or 2; and-   Z is C or O;-   provided that the compound is not:

-   2. The compound of embodiment 1 of formula (Ia):

or a pharmaceutically acceptable salt thereof.

-   3. The compound of embodiment 1 of formula (Ib):

or a pharmaceutically acceptable salt thereof.

-   4. The compound of embodiment 1 of formula (Ic):

or a pharmaceutically acceptable salt thereof.

-   5. The compound of embodiment 1 of formula (Id):

or a pharmaceutically acceptable salt thereof.

-   6. The compound of any of embodiments 1-5, wherein Z is C.-   7. The compound of embodiment 6, wherein n2 is 0 and n3 is 0.-   8. The compound of embodiment 6, wherein one of n2 and n3 is 0 and    the other is 1.-   9. The compound of embodiment 6, wherein n2 is 1 and n3 is 1.-   10. The compound of any of embodiments 1-5, wherein n2 is 1 and Z is    O.-   11. The compound of embodiment 10, wherein n3 is 1.-   12. The compound of embodiment 1 of formula (I-C):

or a pharmaceutically acceptable salt thereof.

-   13. The compound of any of embodiments 1-12, wherein n1 is 1.-   14. The compound of any of embodiments 1-12, wherein n1 is 2.-   15. The compound of any of embodiments 1-12, wherein n1 is 3.-   16. The compound of any of embodiments 1-15, wherein at least two of    R¹, R², R³, and R⁴ are —H.-   17. The compound of any of embodiments 1-15, wherein at least three    of R¹, R², R³, and R⁴ are —H.-   18. The compound of any of embodiments 1-17, wherein the 5- or    6-membered heteroaryl has at least 1 nitrogen ring atom and is    unsubstituted or substituted with 1 group selected from halo, —OH,    —OCH₃, —OCF₃, —NH₂, —NH(CH₃), —N(CH₃)₂, —CH₃, ethyl, —CF₃, and —CN.-   19. The compound of embodiment 18, wherein the heteroaryl is    unsubstituted pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, isoxazolyl,    imidazolyl, or oxazolyl.-   20. The compound of embodiment 18, wherein the heteroaryl is    unsubstituted pyridyl or isoxazolyl.-   21. The compound of any of embodiments 1-16 or 18-20, wherein two    adjacent instances of R¹, R², R³, and R⁴ together form —O—CH₂—O—,    —O—CH(CH₃)—O—, or —O—C(CH₃)₂—O—.-   22. The compound of embodiment 21, wherein two adjacent instances of    R¹, R², R³, and R⁴ together form —O—CH₂—O—.-   23. The compound of any of embodiments 1-22, wherein R^(a) is —H.-   24. The compound of any of embodiments 1-23, wherein R is —H.-   25. The compound of any of embodiments 1-24, wherein each instance    of R⁵ is —F or —CH₃.-   26. The compound of any of embodiments 1-25, wherein each instance    of R⁶ is —F or —CH₃.-   27. The compound of any of embodiments 1-25, wherein each instance    of R⁶ is —CH₃.-   28. The compound of any of embodiments 1-24, 26, or 27, wherein m is    0.-   29. The compound of any of embodiments 1-25, wherein w is 0.-   30. The compound of any of embodiments 1-24, wherein m is 0 and w is    0.-   31. The compound of any of embodiments 1-30, wherein R¹, R², R³, and    R⁴ are independently —H, halo, C₁-C₃ alkyl, —OR⁷ or —CN.-   32. The compound of any of embodiments 1-30, wherein R¹, R², R³, and    R⁴ are independently —H, —F, —CH₃, —OCH₃, or —CN.-   33. A composition comprising a compound according to any one of    embodiments 1 to 32 and a pharmaceutically acceptable carrier,    adjuvant, or vehicle.-   34. A method for treating a neurological or psychiatric disorder in    a patient, comprising administering to said patient an effective    amount of the compound according to any of embodiments 1-32.-   35. The method according to embodiment 34, wherein the neurological    or psychiatric disorder is major depression, schizophrenia, bipolar    disorder, obsessive compulsive disorder (OCD), panic disorder, or    posttraumatic stress disorder (PTSD).-   36. The method according to embodiment 34, wherein the neurological    or psychiatric disorder is bipolar disorder, mania, psychosis, or    schizophrenia.

What is claimed is:
 1. A process for preparing a compound of formula

or a pharmaceutically acceptable salt thereof, comprising: a) combining

with an acid to form

b) separating

into

and c) isolating


2. The process according to claim 1 further comprising forming

by mixing

and a base and isolating


3. The process according to claim 2 further comprising forming

by mixing

with methanesulfonyl chloride and isolating


4. The process according to claim 3 further comprising forming

by mixing

with F and isolating


5. The process according to claim 4 further comprising forming

by reacting

with

and isolating


6. The process according to claim 5 further comprising forming

by mixing

with TBDMSCl and isolating


7. A process for preparing a compound of formula

or a pharmaceutically acceptable salt thereof, comprising: a) combining

with an acid to form

b) separating

into

and c) isolating


8. The process according to claim 7 further comprising forming

by mixing

and a base and isolating


9. The process according to claim 8 further comprising forming

by mixing

with methanesulfonyl chloride and isolating


10. The process according to claim 9 further comprising forming

by mixing

with F⁻ and isolating


11. The process according to claim 10 further comprising forming

by reacting

with

and isolating


12. The process according to claim 11 further comprising forming

by mixing

with TBDMSCl and isolating


13. A process for preparing a compound of formula

or a pharmaceutically acceptable salt thereof, comprising: a) combining

with an acid to form

b) separating

into

and c) isolating


14. The process according to claim 13 further comprising forming

by mixing

and a base and isolating


15. The process according to claim 14 further comprising forming

by mixing

with methanesulfonyl chloride and isolating


16. The process according to claim 15 further comprising forming

by mixing

with F⁻ and isolating


17. The process according to claim 16 further comprising forming

by reacting

with

and isolating


18. The process according to claim 17 further comprising forming

by mixing

with TBDMSCl and isolating


19. A process for preparing a compound of formula

or a pharmaceutically acceptable salt thereof, comprising: a) combining

with an acid to form

b) separating

into

and c) isolating


20. The process according to claim 19 further comprising forming

by mixing

and a base and isolating


21. The process according to claim 20 further comprising forming

by mixing

with methanesulfonyl chloride and isolating


22. The process according to claim 21 further comprising forming

by mixing

with F⁻ and isolating


23. The process according to claim 22 further comprising forming

by reacting

with

and isolating


24. The process according to claim 23 further comprising forming

by mixing

with TBDMSCl and isolating